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CN107446043A - Sclerostin结合剂 - Google Patents

Sclerostin结合剂 Download PDF

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Publication number
CN107446043A
CN107446043A CN201710738235.4A CN201710738235A CN107446043A CN 107446043 A CN107446043 A CN 107446043A CN 201710738235 A CN201710738235 A CN 201710738235A CN 107446043 A CN107446043 A CN 107446043A
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China
Prior art keywords
sclerostin
antibody
seq
cdr
amino acid
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Pending
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CN201710738235.4A
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Inventor
C·帕斯蒂
M·K·罗宾森
K·格雷厄姆
A·J·亨利
K·S·霍夫曼
J·莱瑟姆
A·劳森
H·S·鲁
A·波普尔韦尔
W·沈
D·温克勒
A·G·温特斯
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UCB Pharma SA
Amgen Inc
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UCB Pharma SA
Amgen Inc
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Application filed by UCB Pharma SA, Amgen Inc filed Critical UCB Pharma SA
Publication of CN107446043A publication Critical patent/CN107446043A/zh
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Abstract

提供了与sclerostin蛋白质表位，以及sclerostin结合剂，例如能够与sclerostin结合的抗体相关的组合物和方法。

Description

Sclerostin结合剂
本申请是申请号为201310191210.9、申请日为2006年4月28日的中国发明专利申请的分案申请。
技术领域
一般而言，本发明涉及sclerostin蛋白质包括人sclerostin蛋白质的表位，以及能够与sclerostin或其片段结合的结合剂(例如抗体)。
发明背景
在个体一生中存在骨量变化的2或3个不同阶段(参见Riggs，West J.Med.154:63-77(1991))。第一个阶段在男性和女性中都发生且进展至获得骨峰值。第一个阶段通过由于骨膜附着率的软骨内生长板的线性生长和辐射生长达到。第二个阶段对于松质骨(扁骨例如椎骨和骨盆)约30岁开始且对于骨皮质(例如四肢中发现的长骨)约40岁开始且持续至老年。这个阶段的特征在于慢性骨丢失且在男性和女性中都发生。在女性中，还存在第三个阶段的骨丢失，最可能是由于绝经后的雌激素缺乏。单独在这个阶段时，女性可能丢失来自骨皮质和来自小梁室的另外骨量(参见Riggs，同上)。
骨矿物质含量的丢失可以由广泛多样的条件引起，且可以导致严重的医学问题。例如，骨质疏松症是人中的衰弱性疾病，并且特征在于骨骼骨量和矿物质密度的显著减少，骨结构恶化，包括骨微结构恶化以及受侵袭个体中骨脆性(即，骨强度减少)和对骨折的敏感性的相应增加。在人中的骨质疏松症之前一般为临床骨量减少(骨矿物质密度以大于1个标准差但小于2.5个标准差的程度低于年轻人骨的平均值)，所述临床骨量减少是在美国大约25,000,000人中发现的病症。在美国还有7,000,000－8,000,000名患者已诊断患有临床骨质疏松症(定义为骨矿物质含量以大于2.5个标准差的程度低于成熟年轻人骨)。在人群中的骨质疏松症的频率随着年龄增加。在高加索人中，骨质疏松症在女性中居多，在美国，女性占80％的骨质疏松症患者群。在老年人中增加的脆性和对骨骼骨的骨折的敏感性经由这个群体中更大的意外跌倒危险而加重。髋、腕和椎骨骨折是与骨质疏松症相关的最常见损伤。尤其是髋骨折对于患者是极端不舒服和昂贵的，而且对于女性与高死亡率和发病率相关。
尽管骨质疏松症已视为由于骨量减少的骨折危险增加，但用于骨骼病症的目前可用治疗几乎都不能增加成人的骨密度，并且大多数目前可用治疗主要通过抑制进一步的骨再吸收而不是刺激新骨生成来起作用。雌激素目前被开处方以延缓骨丢失。然而，关于患者是否获得任何长期利益和雌激素对超过75岁的患者是否具有任何影响存在某些争论。此外，雌激素的使用被认为增加乳腺癌和子宫内膜癌的危险。降钙素、骨钙蛋白与维生素K、或高剂量饮食钙连同或不连同维生素D也已建议用于绝经后女性。然而，高剂量的钙通常具有不希望的胃肠副作用，且必须连续监控血清和尿钙水平(例如Khosla和Riggs，MayoClin.Proc.70:978982，1995)。
关于骨质疏松症的其他目前治疗方法包括二膦酸盐(例如，FosamaxTM、ActonelTM、BonvivaTM、ZometaTM、奥帕膦酸盐、奈立膦酸钠、替鲁膦酸钠片、骨磷)、甲状旁腺激素、钙受体拮抗剂(calcilytics)、拟钙剂(calcimimetics)(例如cinacalcet)、他汀类药物、促蛋白合成类固醇、镧和锶盐，以及氟化钠。然而此类治疗通常伴随不希望有的副作用(参见Khosla和Riggs，同上)。
SOST基因的产物sclerostin在硬化性骨化病(sclerosteosis)中不存在，所述硬化性骨化病是特征在于骨过度生长和强致密骨的骨骼疾病(Brunkow等人，Am.J.Hum.Genet.，68:577-589，2001；Balemans等人，Hum.Mol.Genet.，10:537-543，2001)。人sclerostin的氨基酸序列由Brunkow等人(同上)报告且在本文中公开为SEQ ID NO:1。
发明简述
本文公开的是可以用于增加骨形成、骨矿物质密度、骨矿物质含量、骨量(bonemass)、骨质量(bone quality)和骨强度中的至少一种，且因此可以用于治疗广泛多样病症的组合物和方法，在所述病症中骨形成、骨矿物质密度、骨矿物质含量、骨量、骨质量和骨强度中的至少一种的增加是希望的。本发明还提供了本文所述的其他相关优点。
本发明涉及由本文公开的结合剂识别的人sclerostin的区域(表位)，使用这些表位的方法，以及制备此类表位的方法。
本发明还涉及对鉴别为Loop2的sclerostin区域特异的表位，以及与那个区域特异性结合的结合剂。
本发明还涉及对sclerostin的胱氨酸结区域特异的表位，以及与那个区域特异性结合的结合剂例如抗体。
本发明涉及与sclerostin特异性结合的结合剂例如抗体。结合剂可以通过其交叉阻断本文公开的至少一种抗体与sclerostin的结合和/或被本文公开的至少一种抗体交叉阻断结合sclerostin的能力来表征。抗体及其他结合剂还可以通过在如本文公开的“人sclerostin肽表位竞争结合测定法”中其与人sclerostin肽的结合模式来表征。
本发明涉及可以增加哺乳动物中的骨形成、骨矿物质密度、骨矿物质含量、骨量、骨质量和骨强度中的至少一种的结合剂，例如抗体。
本发明涉及在基于细胞的矿化测定法中可以阻断sclerostin的抑制效应的结合剂，例如抗体。
本发明进一步涉及包含通过至少一个二硫键连接的2、3或4个多肽片段并且代表sclerostin的胱氨酸结(cystine-knot)的核心区的多肽构建体，以及能够与其特异性结合的抗体。
本发明涉及获得适合于用作免疫原用于在哺乳动物中产生能够与sclerostin特异性结合的结合剂例如抗体的表位的方法；在某些实施方案中产生的结合剂能够在体内中和sclerostin活性。
本发明涉及当组合物施用于动物时用于诱发对sclerostin特异的抗体的组合物，所述组合物包含具有SEQ ID NO:6、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ IDNO:66、SEQ ID NO:67、SEQ ID NO:68或SEQ ID NO:69的氨基酸序列的多肽。
本发明还涉及当组合物施用于动物时用于诱发对sclerostin特异的抗体的组合物，所述组合物包含基本上由SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4或SEQ ID NO:5的氨基酸序列组成的至少一种多肽；所述组合物可以包含SEQ ID NO:2、SEQ ID NO:3、SEQ IDNO:4和SEQ ID NO:5的氨基酸序列中的至少2种或至少3种；并且所述组合物可以包含SEQID NO:2、SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5中的所有4种氨基酸序列。
本发明进一步涉及当组合物施用于动物时用于诱发对sclerostin特异的抗体的组合物，所述组合物包含具有SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4和SEQ ID NO:5的氨基酸序列的多肽，其中SEQ ID NO:2和4通过在第57和111位的氨基酸处(参考SEQ ID NO:1)的二硫键连接，并且SEQ ID NO:3和5通过(a)在第82和142位的氨基酸处(参考SEQ ID NO:1)的二硫键、和(b)在第86和144位的氨基酸处(参考SEQ ID NO:1)的二硫键中的至少一个来连接；所述多肽可以保留SEQ ID NO:1的人sclerostin的相应多肽区域的三级结构。
本发明还涉及基本上由SEQ ID NO:1的多重截短的人sclerostin蛋白质组成的多肽T20.6，其中SEQ ID NO:1的氨基酸1-50、65-72、91-100、118-137和150-190在所述多肽中不存在；这种多肽可以通过人sclerostin的胰蛋白酶消化来获得，并且蛋白质可以通过HPLC分级分离法来分离。
本发明进一步涉及包含SEQ ID NO:1的氨基酸51-64、73-90、101-117和138-149的人sclerostin的免疫原性部分T20.6，其中所述免疫原性部分包含至少下列一个：
(a)氨基酸57和111之间的二硫键；
(b)氨基酸82和142之间的二硫键；和
(c)氨基酸86和144之间的二硫键；
所述免疫原性部分可以具有这些二硫键中的至少2个；并且所述免疫原性部分可以具有所有3个二硫键。
本发明进一步涉及包含SEQ ID NO:1的氨基酸57-64、73-86、111-117和138-144的人sclerostin的免疫原性部分T20.6衍生物，其中所述免疫原性部分包含至少下列一个：
(a)氨基酸57和111之间的二硫键；
(b)氨基酸82和142之间的二硫键；和
(c)氨基酸86和144之间的二硫键；
所述免疫原性部分可以具有这些二硫键中的至少2个；并且所述免疫原性部分可以具有所有3个二硫键。
本发明再进一步涉及基本上由在C末端和N末端截短的SEQ ID NO:1的人sclerostin蛋白质组成的多肽，其中SEQ ID NO:1的氨基酸1-85和112-190在所述多肽中不存在。
本发明还涉及包含SEQ ID NO:1的氨基酸86-111的人sclerostin的免疫原性部分；所述免疫原性部分可以基本上由连续氨基酸CGPARLLPNAIGRGKWWRPSGPDFRC(SEQ IDNO:6)组成。
本发明进一步涉及包含SEQ ID NO:98的氨基酸92-109的大鼠sclerostin的免疫原性部分；所述免疫原性部分可以基本上由连续氨基酸PNAIGRVKWWRPNGPDFR(SEQ ID NO:96)组成。
本发明再进一步涉及包含SEQ ID NO:98的氨基酸99-120的大鼠sclerostin的免疫原性部分；所述免疫原性部分可以基本上由连续氨基酸KWWRPNGPDFRCIPDRYRAQRV(SEQID NO:97)组成。
本发明涉及生产人sclerostin的免疫原性部分的方法，其包括下列步骤：
(a)处理人sclerostin以达到完全胰蛋白酶消化；
(b)收集如通过以0.2ml/分钟的流速使用0.05％三氟乙酸－溶于0.05％TFA的90％乙腈的线性梯度从反相HPLC柱中洗脱测定的，平均分子量为7,122.0道尔顿(理论质量7121.5的道尔顿)或保留时间为约20.6分钟的胰蛋白酶消化样品；和
(c)纯化免疫原性部分。
本发明涉及产生能够与sclerostin特异性结合的抗体的方法，其包括：
(a)用包含SEQ ID NO:6、SEQ ID NO:63、SEQ ID NO:64、SEQ ID NO:65、SEQ IDNO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:96或SEQ ID NO:97的多肽的组合物免疫动物；
(b)从动物中收集血清；和
(c)从血清中分离能够与sclerostin特异性结合的抗体。
本发明还涉及产生能够与sclerostin特异性结合的抗体的方法，所述方法包括：
(a)用包含多肽T20.6或T20.6衍生物的组合物免疫动物；
(b)从动物中收集血清；和
(c)从血清中分离能够与sclerostin特异性结合的抗体。
本发明进一步涉及检测生物样品中的抗sclerostin抗体的方法，其包括下列步骤
(a)使生物样品与基本上由SEQ ID NO:6、SEQ ID NO:63、SEQ ID NO:64、SEQ IDNO:65、SEQ ID NO:66、SEQ ID NO:67、SEQ ID NO:68、SEQ ID NO:69、SEQ ID NO:96或SEQID NO:97组成的多肽在允许抗体和所述多肽之间形成复合物的条件下接触；和
(b)检测复合物的存在或缺乏，
其中复合物的存在表明生物样品包含抗sclerostin抗体。
本发明还涉及检测生物样品中的抗sclerostin抗体的方法，其包括下列步骤
(a)使生物样品与多肽T20.6或T20.6衍生物在允许抗体和所述多肽之间形成复合物的条件下接触；和
(b)检测复合物的存在或缺乏，
其中复合物的存在表明生物样品包含抗sclerostin抗体。
本发明进一步涉及交叉阻断抗体Ab-A、Ab-B、Ab-C或Ab-D中至少一种与sclerostin蛋白质的结合的sclerostin结合剂，例如抗体。sclerostin结合剂也可以被抗体Ab-A、Ab-B、Ab-C或Ab-D中至少一种交叉阻断与sclerostin的结合。分离的抗体或其抗原结合片段可以是多克隆抗体、单克隆抗体、人源化抗体、人抗体、嵌合抗体等。
本发明进一步涉及被抗体Ab-A、Ab-B、Ab-C或Ab-D中至少一种交叉阻断与sclerostin的结合的sclerostin结合剂，例如抗体。分离的抗体或其抗原结合片段可以是多克隆抗体、单克隆抗体、人源化抗体、人抗体、嵌合抗体等。
本发明进一步涉及交叉阻断抗体1-24(Ab-1至Ab-24)中至少一种与sclerostin蛋白质的结合的sclerostin结合剂，例如分离的抗体。sclerostin结合剂也可以被抗体1-24(Ab-1至Ab-24)中至少一种交叉阻断与sclerostin的结合。分离的抗体或其抗原结合片段可以是多克隆抗体、单克隆抗体、人源化抗体、人抗体或嵌合抗体。
本发明进一步涉及被抗体1-24(Ab-1至Ab-24)中至少一种交叉阻断与sclerostin的结合的sclerostin结合剂，例如分离的抗体；分离的抗体或其抗原结合片段可以是多克隆抗体、单克隆抗体、人源化抗体、人抗体或嵌合抗体。
本发明进一步涉及在“人sclerostin肽表位竞争结合测定法”中显示与人sclerostin肽的结合模式类似于抗体Ab-A、Ab-B、Ab-C或Ab-D中至少一种显示的那种的结合剂，例如分离的抗体；分离的抗体或其抗原结合片段可以是多克隆抗体、单克隆抗体、人源化抗体、人抗体或嵌合抗体。
本发明进一步涉及用于治疗哺乳动物受试者中的低骨形成、低骨矿物质密度、低骨矿物质含量、低骨量、低骨质量和低骨强度中的至少一种的方法，其包括给需要此类治疗的受试者提供抗sclerostin结合剂，其量足以增加骨形成、骨矿物质密度、骨矿物质含量、骨量、骨质量和骨强度中的至少一种，其中所述抗sclerostin结合剂包含抗体或其sclerostin结合片段。
本发明还涉及分离的sclerostin多肽或其片段，其中所述多肽包含6个保守的半胱氨酸残基并且其片段包含SEQ ID NO:2的7－14个氨基酸；SEQ ID NO:3的8－17个氨基酸；SEQ ID NO:4的8－18个残基；和SEQ ID NO:5的6－12个残基，并且所述多肽或其片段通过SEQ ID NO:2和4之间，以及SEQ ID NO:3和5之间的二硫键来稳定；所述多肽或片段可以包含SEQ ID NO:2的10－14个氨基酸；SEQ ID NO:3的14－17个氨基酸；SEQ ID NO:4的13－18个残基；和SEQ ID NO:5的8－12个残基；并且所述多肽或片段可以包含SEQ ID NO:2、SEQID NO:3、SEQ ID NO:4和SEQ ID NO:5。
本文提供了与人sclerostin特异性结合的抗体。抗体的特征在于其交叉阻断本文公开的至少一种抗体与人sclerostin的结合和/或被本文公开的至少一种抗体交叉阻断与人sclerostin的结合的能力。
还提供了可以增加哺乳动物中的骨形成、骨矿物质密度、骨矿物质含量、骨量、骨质量和骨强度中的至少一种的分离的抗体，或其抗原结合片段。
还提供了在基于细胞的矿化测定法中可以阻断sclerostin的抑制效应的分离的抗体，或其抗原结合片段。
还提供了与人sclerostin特异性结合，且具有选自下列SEQ ID NOs的至少一个CDR序列的结合剂例如抗体：39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、78、79、80、81、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、237、238、239、240、241、242、243、244、245、246、247、248、249、250、251、252、253、254、255、256、257、258、259、260、261、262、263、264、265、266、267、268、269、270、271、272、273、274、275、276、277、278、279、280、281、282、283、284、285、286、287、288、289、290、291、292、293、294、295、296、297、298、351、352、353、358、359和360，及其变体，其中所述抗体或其抗原结合片段中和sclerostin。
还提供了与人sclerostin特异性结合，且具有选自下列SEQ ID NOs的至少一个CDR序列的结合剂例如抗体：39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、78、79、80、81、99、100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、237、238、239、240、241、242、243、244、245、246、247、248、249、250、251、252、253、254、255、256、257、258、259、260、261、262、263、264、265、266、267、268、269、270、271、272、273、274、275、276、277、278、279、280、281、282、283、284、285、286、287、288、289、290、291、292、293、294、295、296、297、298、351、352、353、358、359和360，及其变体。
还提供了对蛋白质的体内活性重要的人sclerostin区域。
本发明的这些以及其他方面在参考下列详细描述和附图后将变得显而易见。本文公开的所有参考文献在此整体引入作为参考，如同每个参考文献单独引入一样。
附图简述
图1描述了关于成熟形式(信号肽被切除)的抗人sclerostin和抗小鼠sclerostin抗体Ab-A的轻链(图1A)(SEQ ID NO:23)和重链(图1B)(SEQ ID NO:27)的氨基酸序列。
图2描述了关于成熟形式(信号肽被切除)的抗人sclerostin和抗小鼠sclerostin抗体Ab-B的轻链(图2A)(SEQ ID NO:31)和重链(图2B)(SEQ ID NO:35)的氨基酸序列。
图3描述了关于成熟形式(信号肽被切除)的抗人sclerostin和抗小鼠sclerostin抗体Ab-C的轻链(图3A)(SEQ ID NO:15)和重链(图3B)(SEQ ID NO:19)的氨基酸序列。
图4描述了关于成熟形式(信号肽被切除)的抗人sclerostin和抗小鼠sclerostin抗体Ab-D的轻链(图4A)(SEQ ID NO:7)和重链(图4B)(SEQ ID NO:11)的氨基酸序列。
图5描述了用媒介物、PTH(1-34)、Ab-A或Ab-B处理3周后在小鼠的2个骨骼部位(腰椎和胫骨干骺端)测量的骨矿物质密度。
图6描述了用媒介物、PTH(1-34)或Ab-C处理2周后在小鼠的2个骨骼部位(腰椎和胫骨干骺端)测量的骨矿物质密度。
图7描述了用媒介物或Ab-D处理3周后在小鼠的2个骨骼部位(腰椎和胫骨干骺端)测量的骨矿物质密度。
图8描述了成熟形式(信号肽被切除)的人sclerostin(SEQ ID NO:1)的氨基酸序列。还描述了编码成熟形式的人sclerostin的人sclerostin编码区的核苷酸序列。8个半胱氨酸被编号C1到C8。胱氨酸结由3个二硫键(C1-C5；C3-C7；C4-C8)形成。C2和C6也形成二硫键，然而这个二硫键不是胱氨酸结的部分。
图9描述了人sclerostin的基本结构的示意图。存在N末端臂(从第一个Q到C1)和C末端臂(从C8到末端Y)。在这些臂之间存在胱氨酸结结构(由3个二硫键形成：C1-C5；C3-C7；C4-C8)和称为Loop1、Loop2和Loop3的3个环。Loop1和Loop3的远侧区通过C2-C6二硫键连接。指出了可能的胰蛋白酶切割位点(精氨酸＝R和赖氨酸＝K)。指出了某些可能的AspN切割位点(只显示了天冬氨酸(D)残基)。
图10描述了用胰蛋白酶或AspN消化后人sclerostin的HPLC肽图。指出了通过胰蛋白酶消化产生的人sclerostin肽(T19.2、T20、T20.6和T21-22)，同样指出了通过AspN消化后产生的人sclerostin肽(AspN14.6、AspN18.6和AspN22.7-23.5)。
图11描述了通过胰蛋白酶消化产生的分离的人sclerostin二硫键合肽的序列和质量信息。Seq.pos.＝序列位置。Obs.＝观察到的。观察到的质量通过ESI-LC-MS分析测定。
图12描述了通过AspN消化产生的分离的人sclerostin肽的序列和质量信息。AspN22.7-23.5肽包含4个二硫键。Seq.pos.＝序列位置。Obs.＝观察到的。观察到的质量通过ESI-LC-MS分析测定。
图13显示了通过胰蛋白酶消化产生的4种人sclerostin肽(T19.2、T20、T20.6和T21-22)的线性示意图。
图14显示了通过AspN消化产生的5种人sclerostin肽(AspN14.6、AspN18.6和AspN22.7-23.5)的线性示意图。AspN14.6HPLC峰由不通过任何二硫键连接的3种肽组成。
图15显示了来自基于Biacore的“人sclerostin肽表位竞争结合测定法”的共振单位(Ru)信号。测定了与各种人sclerostin肽(在溶液中)结合的Mab以及与完整成熟形式的人sclerostin(固定在Biacore芯片上)结合的Mab。显示了关于Ab-A的数据。使用的人sclerostin肽是T19.2、T20、T20.6、T21-22、AspN14.6、AspN18.6和AspN22.7-23.5。
图16显示了来自基于Biacore的“人sclerostin肽表位竞争结合测定法”的共振单位(Ru)信号。测定了与各种人sclerostin肽(在溶液中)结合的Mab以及与完整成熟形式的人sclerostin(固定在Biacore芯片上)结合的Mab。显示了关于Ab-B的数据。使用的人sclerostin肽是T19.2、T20、T20.6、T21-22、AspN14.6、AspN18.6和AspN22.7-23.5。
图17显示了来自基于Biacore的“人sclerostin肽表位竞争结合测定法”的共振单位(Ru)信号。测定了与各种人sclerostin肽(在溶液中)结合的Mab以及与完整成熟形式的人sclerostin(固定在Biacore芯片上)结合的Mab。显示了关于Ab-C的数据。使用的人sclerostin肽是T19.2、T20、T20.6、T21-22、AspN14.6、AspN18.6和AspN22.7-23.5。
图18显示了来自基于Biacore的“人sclerostin肽表位竞争结合测定法”的共振单位(Ru)信号。测定了与各种人sclerostin肽(在溶液中)结合的Mab以及与完整成熟形式的人sclerostin(固定在Biacore芯片上)结合的Mab。显示了关于Ab-D的数据。使用的人sclerostin肽是T19.2、T20、T20.6、T21-22、AspN14.6、AspN18.6和AspN22.7-23.5。
图19显示了人sclerostin的2种Mab结合表位。图19A显示了关于Ab-A和Ab-B与人sclerostin结合的Loop2表位的序列(SEQ ID NO:6)。图19B显示了关于Ab-C和Ab-D与人sclerostin结合的T20.6表位的序列、二硫键合和示意图(SEQ ID NO:2-5)。
图20描述了用胰蛋白酶消化后的人sclerostin的HPLC肽图。图20A显示了人sclerostin Ab-D复合物的消化。图20B显示了单独的人sclerostin的消化。指出了T19.2、T20、T20.6和T21-22肽的峰。
图21显示了关于Ab-D与人sclerostin结合的“T20.6衍生物1(胱氨酸结+4臂)”表位的序列、二硫键合和示意图(SEQ ID NO:70-73)。
图22显示来自用于鉴定抗sclerostin中和Mab的MC3T3-E1-BF成骨细胞系矿化测定法的结果。使用1μg/ml的小鼠sclerostin(Scl)。使用10和5μg/ml的单克隆抗体。通过测量钙来定量矿化(各种类型的不溶性磷酸钙)程度。
图23显示来自用于鉴定抗sclerostin中和Mab的MC3T3-E1-BF成骨细胞系矿化测定法的结果。使用1μg/ml的人sclerostin(Scl)。使用8和4μg/ml的单克隆抗体。通过测量钙来定量矿化(各种类型的不溶性磷酸钙)程度。
图24显示来自用于鉴定抗sclerostin中和Mab的MC3T3-E1-BF成骨细胞系矿化测定法的结果。使用1μg/ml的人sclerostin(Scl)。使用10μg/ml的单克隆抗体。通过测量钙来定量矿化(各种类型的不溶性磷酸钙)程度。
图25描述了来自炎症诱导的骨丢失SCID小鼠模型的结果。Ab-A的处理保护小鼠不受与结肠炎有关的炎症相关性骨丢失，当测量为总骨矿物质密度(图25A)、椎骨密度(图25B)和股骨密度(图25C)时。
发明详述
本发明涉及包含由与全长sclerostin结合的抗体识别的表位的人sclerostin蛋白质区域，以及制备和使用这些表位的方法。本发明还提供了与sclerostin或sclerostin的部分特异性结合的结合剂(例如抗体)，以及使用此类结合剂的方法。结合剂用于阻断或削弱人sclerostin与一种或多种配体的结合。
重组人sclerostin/SOST从R&D Systems(Minneapolis，MN，USA；2006目录#1406-ST-025)商购可得。此外，重组小鼠sclerostin/SOST从R&D Systems(Minneapolis，MN，USA；2006目录#1589-ST-025)商购可得。研究级sclerostin结合单克隆抗体从R&D Systems(Minneapolis，MN，USA；小鼠单克隆：2006目录#MAB1406；大鼠单克隆：2006目录#MAB1589)商购可得。美国专利号6,395,511和6,803,453以及美国专利公开20040009535和20050106683一般性涉及抗sclerostin抗体。
如本文使用的，术语人sclerostin意欲包括SEQ ID NO:1的蛋白质及其等位基因变体。Sclerostin可以通过使用肝素HP柱、使用盐梯度洗脱宿主细胞培养液的过滤上清液从293T宿主细胞纯化，所述293T宿主细胞已被编码sclerostin的基因转染。制备和使用阳离子交换色谱法的进一步纯化在实施例1和2中描述。
如本文定义的，本发明的结合剂优选是抗体。术语“抗体”指完整抗体或其结合片段。抗体可以包含完整的抗体分子(包括具有全长重链和/或轻链的多克隆、单克隆、嵌合、人源化、或人抗体)，或包含其抗原结合片段。抗体片段包括F(ab')2、Fab、Fab’、Fv、Fc和Fd片段，且可以掺入单结构域抗体、单链抗体、特大型抗体(maxibodies)、微型抗体(minibody)、胞内抗体、双链抗体、三链抗体、四链抗体、v-NAR和双-scFv内(参见例如Hollinger和Hudson，2005，Nature Biotechnology，23，9，1126-1136)。抗体多肽还在美国专利号6,703,199中公开，包括纤连蛋白多肽单体(monobody)。其他抗体多肽在美国专利公开2005/0238646中公开，它们是单链多肽。
来源于抗体的抗原结合片段可以例如根据常规方法通过抗体的蛋白水解作用获得，例如完整抗体的胃蛋白酶或木瓜蛋白酶消化。例如，抗体片段可以通过用胃蛋白酶酶促切割抗体来产生，以提供称为F(ab')2的5S片段。这种片段可以使用硫醇还原剂进一步切割以产生3.5S Fab’单价片段。任选地，切割反应可以使用适合于巯基的封闭基来进行，所述巯基由二硫键切割产生。作为可替代方法，使用木瓜蛋白酶的酶促切割直接产生2个单价Fab片段和Fc片段。这些方法例如由Goldenberg，美国专利号4,331,647，Nisonoff等人，Arch.Biochem.Biophys.89:230，1960；Porter，Biochem.J.73:119，1959；Edelman等人，在Methods in Enzymology 1:422(Academic Press 1967)中；以及由Andrews，S.M.和Titus，J.A.在Current Protocols in Immunology中(Coligan J.E.,等人，eds)，John Wiley&Sons，New York(2003)第2.8.1-2.8.10页和第2.10A.1-2.10A.5页描述。也可以使用用于切割抗体的其他方法，例如分开重链以形成单价轻-重链片段(Fd)，片段的进一步切割，或其他酶促、化学或遗传技术，条件是片段能与由完整抗体识别的抗原结合。
抗体片段也可以是任何合成或遗传工程化的蛋白质。例如，抗体片段包括由轻链可变区组成的分离的片段，由重和轻链可变区组成的“Fv”片段，其中轻和重可变区通过肽连接子连接的重组单链多肽分子(scFv蛋白质)。
另一种形式的抗体片段是包含抗体的一个或多个互补决定区(CDR)的肽。CDR(也称为“最小识别单位”、或“高变区”)可以通过构建编码目的CDR的多核苷酸来获得。此类多核苷酸例如通过使用聚合酶链式反应使用产生抗体的细胞的mRNA作为模板合成可变区来制备(参见，例如，Larrick等人，Methods：A Companion to Methods in Enzymology 2:106，1991；Courtenay-Luck，“Genetic Manipulation of Monoclonal Antibodies,”在Monoclonal Antibodies：Production，Engineering and Clinical Application中，Ritter等人，(eds.)，第166页(Cambridge University Press 1995)；以及Ward等人，“Genetic Manipulation and Expression of Antibodies,”在Monoclonal Antibodies：Principles and Applications中，Birch等人，(eds.)，第137页(Wiley-Liss，Inc.1995))。
因此，在一个实施方案中，结合剂包含如本文所述的至少一个CDR。结合剂可以包含如本文所述的至少2、3、4、5或6个CDR。结合剂可以进一步包含本文所述抗体的至少一种可变区结构域。可变区结构域可以具有任何大小或氨基酸组成，且一般将包含负责与人sclerostin结合的至少一个CDR序列，例如本文具体描述的CDR-H1、CDR-H2、CDR-H3和/或轻链CDRs且与一个或多个构架序列相邻或在其框内(in frame)。一般而言，可变(V)区结构域可以是免疫球蛋白重(VH)和/或轻(VL)链可变结构域的任何合适排列。因此，例如，V区结构域可以是单体且可以是VH或VL结构域，其能够如下所述以至少等于1x 10-7M或更低的亲和力独立地结合人sclerostin。可替代地，V区结构域可以是二聚体且包含VH-VH、VH-VL或VL-VL二聚体。V区二聚体包含可以非共价结合的至少一条VH和至少一条VL链(下文称为FV)。必要时，链可以直接共价偶联，例如经由2个可变结构域之间的二硫键，或通过连接子例如肽连接子偶联，以形成单链Fv(scFV)。
可变区结构域可以是任何天然存在的可变结构域或其改造形式。改造形式意指已使用重组DNA改造技术制备的可变区结构域。此类改造形式包括例如通过特异性抗体的氨基酸序列中的插入、删除或变化由特异性抗体可变区制备的那些。具体例子包括包含至少一个CDR和任选地一个或多个构架氨基酸来自第一种抗体以及可变区结构域的其余部分来自第二种抗体的改造的可变区结构域。
可变区结构域可以在C末端氨基酸处与至少一种其他抗体结构域或其片段共价附着。因此，例如，可变区结构域中存在的VH结构域可以与免疫球蛋白CH1结构域或其片段连接。类似地，VL结构域可以与CK结构域或其片段连接。以这种方式，例如，抗体可以是Fab片段，其中抗原结合结构域包含在其C末端处分别与CH1和CK结构域共价连接的结合的VH和VL结构域。CH1结构域可以用更多的氨基酸延伸，例如以提供如Fab’片段中发现的铰链区或铰链区结构域的部分，或提供更多的结构域，例如抗体CH2和CH3结构域。
如本文描述的，结合剂包含这些CDR中的至少一个。例如，一个或多个CDR可以掺入已知抗体构架区内(IgG1，IgG2等)，或与合适媒介物缀合以增加其半衰期。合适媒介物包括但不限于Fc、聚乙二醇(PEG)、白蛋白、转铁蛋白等。这些和其他合适媒介物是本领域已知的。此类缀合的CDR肽可以是单体、二聚体、四聚体或其他形式。在一个实施方案中，一种或多种水溶性聚合物在结合剂的一个或多个特定位置处例如在氨基末端处结合。
在某些优选实施方案中，结合剂包含一种或多种水溶性聚合物附着物，包括但不限于，聚乙二醇、聚氧乙烯二醇、或聚丙二醇。参见，例如，美国专利号4,640,835、4,496,689、4,301,144、4,670,417、4,791,192和4,179,337。在某些实施方案中，结合剂衍生物包含一种或多种单甲氧基-聚乙二醇、葡聚糖、纤维素、或其他基于碳水化合物的聚合物、聚(N-乙烯吡咯烷酮)聚乙二醇、丙二醇同聚物、聚氧化丙烯/氧化乙烯共聚物、聚氧乙基化多元醇(例如丙三醇)和聚乙烯醇，以及此类聚合物的混合物。在某些实施方案中，一种或多种水溶性聚合物随机附着至一条或多条侧链。在某些实施方案中，PEG可以用于改善结合剂例如抗体的治疗能力。某些此类方法例如在美国专利号6,133,426中讨论，所述专利为了任何目的在此引入作为参考。
应当理解本发明的结合剂可以具有至少一个氨基酸置换，条件是结合剂保留结合特异性。因此，关于结合剂结构的修饰包含在本发明的范围内。这些可以包括不破坏结合剂的sclerostin结合能力的保守或非保守性氨基酸置换。保守性氨基酸置换可以包含非天然存在的氨基酸残基，这一般通过化学肽合成而不是通过在生物系统中合成而掺入。这些包括肽模拟物(peptidomimetics)和其他反向或倒转形式的氨基酸部分。保守性氨基酸置换还可以涉及用标准化残基置换天然氨基酸残基，从而使得对那个位置处的氨基酸残基的极性或电荷只有很小的影响或没有影响。
非保守性置换可以涉及一类氨基酸或氨基酸模拟物的成员交换成具有不同物理性质(例如大小、极性、疏水性、电荷)的另一类的成员。此类置换的残基可以引入与非人抗体同源的人抗体区域内，或分子的非同源区域内。
此外，本领域技术人员可以产生在每个所需氨基酸残基处包含单个氨基酸置换的测试变体。变体随后可以使用本领域技术人员已知的活性测定法来筛选。此类变体可以用于收集关于合适变体的信息。例如，如果发现特定氨基酸残基的变化导致破坏、不希望地减少、或不合适的活性，那么具有此类变化的变体可以被避免。换言之，基于由此类常规实验收集的信息，本领域技术人员可以容易地确定其中应当避免单独的或与其他突变组合的置换的氨基酸。
本领域技术人员将能够使用众所周知的技术确定如本文所述的多肽的合适变体。在某些实施方案中，本领域技术人员可以鉴定通过靶向被认为对活性不重要的区域可以进行改变而不破坏活性的分子的合适区域。在某些实施方案中，可以鉴定在类似多肽中是保守的分子残基和部分。在某些实施方案中，甚至可以在对生物活性或结构可能重要的区域实施保守氨基酸置换而不破坏生物活性或不会不利地影响多肽结构。
另外，本领域技术人员可以检查鉴定类似多肽中对活性或结构重要的残基的结构-功能研究。鉴于此类比较，可以预测蛋白质中氨基酸残基的重要性，所述氨基酸残基对应在类似蛋白质中对活性或结构重要的氨基酸残基。本领域技术人员可以选择对于此类预测重要的氨基酸残基的化学类似的氨基酸置换。
本领域技术人员还可以分析3维结构以及与类似多肽中的那种结构相关的氨基酸序列。鉴于此类信息，本领域技术人员可以预测关于其3维结构的抗体的氨基酸残基比对。在某些实施方案中，本领域技术人员可以选择不对预测在蛋白质表面上的氨基酸残基进行基团变化，因为此类残基可能涉及与其他分子的重要相互作用。
众多科学出版物已致力于二级结构的预测。参见Moult J.，Curr.Op.inBiotech.，7(4):422-427(1996)，Chou等人，Biochemistry，13(2):222-245(1974)；Chou等人，Biochemistry，113(2):211-222(1974)；Chou等人，Adv.Enzymol.Relat.AreasMol.Biol.，47:45-148(1978)；Chou等人，Ann.Rev.Biochem.，47:251-276和Chou等人，Biophys.J.，26:367-384(1979)。此外，计算机程序目前可用于帮助预测二级结构。预测二级结构的一种方法基于同源性建模。例如，具有大于30％的序列同一性，或大于40％的相似性的2种多肽或蛋白质通常具有类似的结构拓扑学。近来发展的蛋白质结构数据库(PDB)已提供增强的二级结构可预测性，包括多肽或蛋白质结构内可能的折叠数目。参见Holm等人，Nucl.Acid.Res.，27(1):244-247(1999)。已建议(Brenner等人，Curr.Op.Struct.Biol.，7(3):369-376(1997))在给定多肽或蛋白质中存在有限数目的折叠，并且一旦关键数目的结构已确定，那么结构预测将明显变得更精确。
预测二级结构的另外方法包括“穿线(threading)”(Jones，D.，Curr.Opin.Struct.Biol.，7(3):377-87(1997)；Sippl等人，Structure，4(1):15-19(1996))，“特征分析(profile analysis)”(Bowie等人，Science，253:164-170(1991)；Gribskov等人，Meth.Enzym.，183:146-159(1990)；Gribskov等人，Proc.Nat.Acad.Sci.，84(13):4355-4358(1987))，和“进化连锁(evolutionary linkage)”(参见Holm，同上(1999)，和Brenner，同上(1997))。
在某些实施方案中，结合剂的变体包括其中与亲本多肽的氨基酸序列相比糖基化位点的数目和/或类型已改变的糖基化变体。在某些实施方案中，变体包含比天然蛋白质数目更多或更少的N连接糖基化位点。N连接糖基化位点的特征在于下列序列：Asn-X-Ser或Asn-X-Thr，其中指定为X的氨基酸残基可以是除脯氨酸以外的任何氨基酸残基。创造这种序列的氨基酸残基置换提供了用于添加N连接糖链的潜在新位点。可替代地，消除这种序列的置换将去除现有的N连接糖链。还提供了N连接糖链的重排，其中一个或多个N连接糖基化位点(一般是天然存在的那些)被消除并且一个或多个新N连接位点被创造。另外优选的抗体变体包括半胱氨酸变体，其中与亲本氨基酸序列比较一个或多个半胱氨酸残基被删除或以另一种氨基酸(例如丝氨酸)置换。当抗体必须重折叠成生物学活性构象时，例如分离不溶性包含体后，半胱氨酸变体可能是有用的。半胱氨酸变体一般具有比天然蛋白质更少的半胱氨酸残基，并且一般具有偶数数目以最小化由不成对的半胱氨酸引起的相互作用。
所需氨基酸置换(无论是保守的还是不保守的)可以由本领域技术人员在此类置换需要时进行确定。在某些实施方案中，氨基酸置换可以用于鉴定针对sclerostin的抗体的重要残基，或增加或减少如本文所述的针对sclerostin的抗体的亲和力。
根据某些实施方案，优选的氨基酸置换是下列那些：(1)减少对蛋白水解的敏感性，(2)减少对氧化的敏感性，(3)改变用于形成蛋白质复合物的结合亲和力，(4)改变结合亲和力，和/或(4)给予或修饰关于此类多肽的其他生理化学或功能特性。根据某些实施方案，单个或多个氨基酸置换(在某些实施方案中，保守性氨基酸置换)可以在天然存在的序列中(在某些实施方案中，在形成分子间接触的结构域外的多肽部分中)进行。在某些实施方案中，保守性氨基酸置换一般基本上不改变亲本序列的结构特征(例如，替换氨基酸不应趋向破坏亲本序列中存在的螺旋，或破裂亲本序列特有的其他类型的二级结构)。本领域公认的多肽二级和三级结构的例子在Proteins，Structures and Molecular Principles(Creighton，Ed.，W.H.Freeman and Company，New York(1984))；Introduction toProtein Structure(C.Branden和J.Tooze，eds.，Garland Publishing，New York，N.Y.(1991))；以及Thornton等人，Nature 354:105(1991)中得到描述，所述参考文献各自引入本文作为参考。
在某些实施方案中，本发明的结合剂可以与聚合物、脂质或其他部分化学结合。
结合剂可以包含掺入生物相容性构架结构内的本文所述的至少一个CDR。在一个例子中，生物相容性构架结构包含足以形成构象稳定的结构支撑、或构架、或支架的多肽或其部分，其能够显示在局部表面区域中与抗原结合的一种或多种氨基酸序列(例如，CDR、可变区等)。此类结构可以是天然存在的多肽或多肽“折叠”(结构基序)，或可以具有相对于天然存在的多肽或折叠的一种或多种修饰，例如氨基酸添加、删除或置换。这些支架可以来源于任何物种(或超过一种的物种)的多肽，例如人、其他哺乳动物、其他脊椎动物、无脊椎动物、植物、细菌或病毒。
生物相容性构架结构一般基于除免疫球蛋白结构域以外的蛋白质支架或骨架。例如，可以使用基于纤连蛋白、锚蛋白、lipocalin、新制癌菌素(neocarzinostain)、细胞色素b、CP1锌指、PST1、卷曲螺旋、LACI-D1、Z结构域和tendramisat结构域的那些(参见例如，Nygren和Uhlen，1997，Current Opinion in Structural Biology，7，463-469)。
在优选实施方案中，应当理解本发明的结合剂包括本文所述的人源化抗体。人源化抗体例如本文所述的那些可以使用本领域技术人员已知的技术产生(Zhang，W.,等人，Molecular Immunology.42(12):1445-1451，2005；Hwang W.等人，Methods.36(1):35-42，2005；Dall'Acqua WF,等人，Methods 36(1):43-60，2005；和Clark，M.，ImmunologyToday.21(8):397-402，2000)。
另外，本领域技术人员将认识到合适的结合剂包括这些抗体的部分，例如如本文具体公开的CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3中的一个或多个。CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3区域中的至少一个可以具有至少一个氨基酸置换，条件是结合剂保留未置换CDR的结合特异性。结合剂的非CDR部分可以是非蛋白质分子，其中结合剂交叉阻断本文公开的抗体与sclerostin的结合和/或中和sclerostin。结合剂的非CDR部分可以是非蛋白质分子，其中结合剂在“人sclerostin肽表位竞争结合测定法”中显示与人sclerostin肽的结合模式类似于至少一种下列抗体显示的那种：Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24，和/或中和sclerostin。结合剂的非CDR部分可以由氨基酸组成，其中结合剂是重组结合蛋白或合成肽，并且所述重组结合蛋白交叉阻断本文公开抗体与sclerostin的结合和/或中和sclerostin。结合剂的非CDR部分可以由氨基酸组成，其中结合剂是重组结合蛋白，并且所述重组结合蛋白在“人sclerostin肽表位竞争结合测定法”(下文描述)中显示与人sclerostin肽的结合模式类似于至少一种下列抗体显示的那种：Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24，和/或中和sclerostin。
当抗体包含如上所述的CDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2和CDR-L3中的一个或多个时，它可以通过由包含编码这些序列的DNA的宿主细胞表达来获得。编码每个CDR序列的DNA可以在CDR氨基酸序列的基础上测定，且适当时使用寡核苷酸合成技术、定点诱变和聚合酶链式反应(PCR)技术与任何所需的抗体可变区构架和恒定区DNA序列一起合成。编码可变区构架和恒定区的DNA对于本领域技术人员由遗传序列数据库例如可广泛获得。上述每个CDR一般将位于可变区构架中根据Kabat编号系统在重链的位置31-35(CDR-H1)、50-65(CDR-H2)和95-102(CDR-H3)和轻链的位置24-34(CDR-L1)、50-56(CDR-L2)和89-97(CDR-L3)处(Kabat等人，1987在Sequences of Proteins ofImmunological Interest中，U.S.Department of Health and Human Services，NIH，USA)。
一旦被合成，编码本发明抗体或其片段的DNA就可以使用许多已知表达载体根据用于核酸切除、连接、转化和转染的各种众所周知操作中的任何一种进行增殖和表达。因此，在某些实施方案中抗体片段的表达在原核细胞例如大肠杆菌(Escherichia coli)中可能是优选的(参见例如，Pluckthun等人，1989Methods Enzymol.178:497-515)。在某些其他实施方案中，抗体或其片段的表达在真核宿主细胞中可能是优选的，包括酵母(例如酿酒酵母(Saccharomyces cerevisiae)、粟酒裂殖酵母(Schizosaccharomyces pombe)和巴斯德毕赤酵母(Pichia pastoris))、动物细胞(包括哺乳动物细胞)或植物细胞。合适的动物细胞的例子包括但不限于骨髓瘤(例如小鼠NSO系)、COS、CHO、或杂交瘤细胞。植物细胞的例子包括烟草、玉米、大豆和水稻细胞。
包含编码抗体可变和/或恒定区的DNA的一种或多种可复制的表达载体可以被制备并用于转化合适的细胞系，例如非生产性骨髓瘤细胞系，例如小鼠NSO系，或其中抗体生产将发生的细菌例如大肠杆菌(E.coli)。为了获得有效转录和翻译，每种载体中的DNA序列应当包括与可变结构域序列可操作地连接的合适的调节序列，特别是启动子和前导序列。用于以这种方式生产抗体的具体方法一般是众所周知和常规使用的。例如，基本分子生物学操作由Maniatis等人，(Molecular Cloning，A Laboratory Manual，第二版，ColdSpring Harbor Laboratory，New York，1989；还参见Maniatis等人，第三版，Cold SpringHarbor Laboratory，New York,(2001))描述。DNA测序可以如Sanger等人，(PNAS 74:5463,(1977))和Amersham International plc测序手册中描述的进行，并且定点诱变可以根据本领域已知方法来进行(Kramer等人，Nucleic Acids Res.12:9441,(1984)；KunkelProc.Natl.Acad.Sci.USA 82:488-92(1985)；Kunkel等人，Methods in Enzymol.154:367-82(1987)；the Anglian Biotechnology Ltd handbook)。另外，众多出版物描述了适合于通过DNA操作、表达载体制备以及合适细胞的转化和培养来制备抗体的技术(Mountain A和Adair，J R in Biotechnology and Genetic Engineering Reviews(ed.Tombs，M P，10，Chapter 1，1992，Intercept，Andover，UK)；“Current Protocols in MolecularBiology”，1999，F.M.Ausubel(ed.)，Wiley Interscience，New York)。
当希望改善包含一个或多个上述CDR的根据本发明的抗体的亲和力时，可以通过众多亲和力成熟方案来获得，包括维持CDR(Yang等人，J.Mol.Biol.，254，392-403，1995)、链改组(Marks等人，Bio/Technology，10，779-783，1992)、使用大肠杆菌的突变菌株(Low等人，J.Mol.Biol.，250，350-368，1996)、DNA改组(Patten等人，Curr.Opin.Biotechnol.，8，724-733，1997)、噬菌体展示(Thompson等人，J.Mol.Biol.，256，7-88，1996)和性别PCR(Crameri,等人，Nature，391，288-291，1998)。所有这些亲和力成熟方法由Vaughan等人(Nature Biotechnology，16，535-539，1998)讨论。
根据本发明的其他抗体可以通过如本文所述和本领域已知的常规免疫接种和细胞融合操作来获得。本发明的单克隆抗体可以使用各种已知技术来产生。一般而言，与特定抗原结合的单克隆抗体可以通过本领域技术人员已知的方法来获得(参见，例如，Kohler等人，Nature256:495，1975；Coligan等人，(eds.)，Current Protocols in Immunology，1:2.5.12.6.7(John Wiley&Sons 1991)；美国专利号RE 32,011，4,902,614，4,543,439和4,411,993；Monoclonal Antibodies，Hybridomas：A New Dimension in BiologicalAnalyses，Plenum Press，Kennett，McKearn,和Bechtol(eds.)(1980)；以及Antibodies：ALaboratory Manual，Harlow和Lane(eds.)，Cold Spring Harbor Laboratory Press(1988)；Picksley等人，“Production of monoclonal antibodies against proteinsexpressed in E.coli,”在DNA Cloning 2：Expression Systems中，第二版，Glover等人，(eds.)，第93页(Oxford University Press1995))。抗体片段可以使用任何合适的标准技术例如蛋白水解消化，或任选地通过蛋白水解消化(例如使用木瓜蛋白酶或胃蛋白酶)随后为二硫键的轻度还原和烷化由此衍生。可替代地，此类片段还可以通过如本文所述的重组遗传工程技术来产生。
单克隆抗体可以根据本领域已知和本文描述的方法通过用包含SEQ ID NO:1的人sclerostin或其片段的免疫原注射动物，例如大鼠、仓鼠、兔、或优选地小鼠，包括例如转基因或敲除的动物来获得。特异性抗体产生的存在可以在最初注射后和/或在加强注射后，通过获得血清样品且使用本领域已知和本文描述的几种免疫检测方法中的任何一种检测与人sclerostin或肽结合的抗体的存在进行监控。从产生所需抗体的动物中取出淋巴样细胞，最通常地来自脾或淋巴结的细胞，以获得B淋巴细胞。B淋巴细胞随后与药物致敏的骨髓瘤细胞融合配偶体融合，优选与被免疫动物是同基因的且任选地具有其他所需特性(例如，不能表达内源性Ig基因产物的任何配偶体，例如P3X63-Ag8.653(ATCC No.CRL 1580)；NSO，SP20)，以产生杂交瘤，这是永生的真核细胞系。淋巴样(例如脾)细胞和骨髓瘤细胞可以与膜融合促进剂例如聚乙二醇或非离子型去污剂组合数分钟，随后以低密度在支持杂交瘤细胞但不支持未融合的骨髓瘤细胞生长的选择性培养基上铺板。优选的选择性培养基是HAT(次黄嘌呤、氨基蝶呤、胸苷)。在足够时间通常为约1至2周后，观察到细胞集落。分离单个集落，且可以使用本领域已知和本文描述的各种免疫测定法中的任何一种测试由细胞产生的抗体与人sclerostin的结合活性。克隆杂交瘤(例如通过有限稀释克隆法或通过软琼脂斑分离)，且选择并培养产生对sclerostin特异的抗体的阳性克隆。来自杂交瘤培养的单克隆抗体可以从杂交瘤培养物的上清液中分离。用于生产鼠类单克隆抗体的可替代方法是将杂交瘤细胞注射到同基因小鼠的腹膜腔内，例如已处理(例如姥鲛烷预处理的)以促进包含单克隆抗体的腹水形成的小鼠。单克隆抗体可以通过各种良好建立的技术进行分离和纯化。此类分离技术包括用A蛋白琼脂糖的亲和色谱法、大小排阻色谱法和离子交换色谱法(参见例如Coligan在第2.7.1-2.7.12页和第2.9.1-2.9.3页；Baines等人，“Purification ofImmunoglobulin G(IgG),”在Methods in Molecular Biology中，第10卷，第79-104页(TheHumana Press，Inc.1992))。单克隆抗体可以通过亲和色谱法使用基于抗体的具体特性(例如重或轻链同种型、结合特异性等)选择的合适配体进行纯化。固定在固体载体上的合适配体的例子包括A蛋白、G蛋白、抗恒定区(轻链或重链)抗体、抗独特型抗体、和TGF-β结合蛋白、或其片段或变体。
本发明的抗体还可以是人单克隆抗体。人单克隆抗体可以通过本领域普通技术人员熟悉的许多技术来产生。此类方法包括但不限于，人外周血细胞(例如包含B淋巴细胞)的EB病毒(EBV)转化、人B细胞的体外免疫接种、携带插入的人免疫球蛋白基因的来自免疫转基因小鼠的脾细胞融合、从人免疫球蛋白V区噬菌体文库中分离、或如本领域已知和基于本文公开内容的其他操作。例如，人单克隆抗体可以由转基因小鼠获得，所述转基因小鼠已进行改造以响应抗原攻击而产生特异性人抗体。用于由转基因小鼠获得人抗体的方法例如由Green等人，Nature Genet.7:13，1994；Lonberg等人，Nature 368:856，1994；Taylor等人，Int.Immun.6:579，1994；美国专利号5,877,397；Bruggemann等人，1997Curr.Opin.Biotechnol.8:455-58；Jakobovits等人，1995Ann.N.Y.Acad.Sci.764:525-35描述。通过这种技术将人重和轻链基因座的元件引入来源于胚胎干细胞系的小鼠品系内，所述胚胎干细胞系包含靶向断裂的内源性重链和轻链基因座(同样参见Bruggemann等人，Curr.Opin.Biotechnol.8:455-58(1997))。例如，人免疫球蛋白转基因可以是小基因构建体、或在酵母人工染色体上的转基因座(transloci)，其在小鼠淋巴样细胞中经历B细胞特异性DNA重排和高突变。人单克隆抗体可以通过免疫转基因小鼠来获得，所述转基因小鼠随后可以产生对sclerostin特异的人抗体。免疫转基因小鼠的淋巴样细胞可以根据本文所述方法用于产生分泌人抗体的杂交瘤。包含人抗体的多克隆血清还可以从免疫动物的血液中获得。
用于产生本发明的人抗体的另一种方法包括通过EBV转化使人外周血细胞永生。参见例如美国专利号4,464,456。产生与sclerostin特异性结合的单克隆抗体的此类永生化B细胞系(或类淋巴母细胞系)可以通过如本文提供的免疫检测方法例如ELISA进行鉴定，随后通过标准克隆技术进行分离。产生抗sclerostin抗体的类淋巴母细胞系的稳定性可以根据本领域已知方法(参见，例如，Glasky等人，Hybridoma8:377-89(1989))通过使转化的细胞系与鼠类淋巴瘤融合以产生小鼠-人杂交细胞系得到改善。产生人单克隆抗体的另一种方法是体外免疫接种，这包括用人sclerostin预处理人脾B细胞，随后使预处理的B细胞与异杂交(heterohybrid)融合配偶体融合。参见，例如，Boerner等人，1991J.Immunol.147:86-95。
在某些实施方案中，产生抗人sclerostin抗体的B细胞被选择，且轻链和重链可变区根据本领域已知(WO 92/02551；美国专利5,627,052；Babcook等人，Proc.Natl.Acad.Sci.USA 93:7843-48(1996))和本文描述的分子生物学技术由B细胞进行克隆。来自免疫动物的B细胞可以通过选择产生与sclerostin特异性结合的抗体的细胞从脾、淋巴结或外周血样品中分离。B细胞还可以从人中例如从外周血样品中分离。用于检测产生具有所需特异性的抗体的单一B细胞的方法是本领域众所周知的，例如通过空斑形成、荧光激活细胞分选、体外刺激随后检测特异性抗体等。用于选择产生特异性抗体的B细胞的方法包括，例如在包含人sclerostin的软琼脂中制备B细胞的单细胞悬浮液。通过B细胞产生的特异性抗体与抗原结合导致形成复合物，所述复合物作为免疫沉淀物可能是看得见的。选择产生所需抗体的B细胞后，特异性抗体基因可以根据本领域已知和本文所述方法通过分离和扩增DNA或mRNA进行克隆。
用于获得本发明抗体的另外方法是经由噬菌体展示。参见，例如，Winter等人，1994Annu.Rev.Immunol.12:433-55；Burton等人，1994Adv.Immunol.57:191-280。人或鼠类免疫球蛋白可变区基因组合文库可以在噬菌体载体中制备，所述噬菌体载体可以进行筛选以选择与TGF-β结合蛋白或其变体或片段特异性结合的Ig片段(Fab、Fv、sFv、或其多聚体)。参见，例如，美国专利号5,223,409；Huse等人，1989Science 246:1275-81；Sastry等人，Proc.Natl.Acad.Sci.USA86:5728-32(1989)；Alting-Mees等人，Strategies inMolecular Biology3:1-9(1990)；Kang等人，1991Proc.Natl.Acad.Sci.USA 88:4363-66；Hoogenboom等人，1992J.Molec.Biol.227:381-388；Schlebusch等人，1997 Hybridoma 16:47-52以及其中引用的参考文献。例如，包含编码Ig可变区片段的多个多核苷酸序列的文库可以插入丝状噬菌体例如M13或其变体的基因组内，与编码噬菌体外壳蛋白的序列按读码框融合。融合蛋白可以是外壳蛋白与轻链可变区结构域和/或重链可变区结构域的融合。根据某些实施方案，免疫球蛋白Fab片段还可以在噬菌体颗粒上展示(参见，例如，美国专利号5,698,426)。
免疫球蛋白重和轻链cDNA表达文库还可以在λ噬菌体中制备，例如使用λlmmunoZapTM(H)和λImmunoZapTM(L)载体(Stratagene，La Jolla，California)。简言之，mRNA从B细胞群中分离，并用于在λImmunoZap(H)和λImmunoZap(L)载体中制备免疫球蛋白重和轻链cDNA表达文库。这些载体可以单独筛选或共表达以形成Fab片段或抗体(参见Huse等人，同上；还参见Sastry等人，同上)。阳性空斑随后可以转变成允许从大肠杆菌高水平表达单克隆抗体片段的非裂解性质粒。
在一个实施方案中，在杂交瘤中，表达目的单克隆抗体的基因的可变区使用核苷酸引物进行扩增。这些引物可以由本领域普通技术人员合成，或可以由商购可得来源购买。(参见，例如，Stratagene(La Jolla，California)，它出售用于小鼠和人可变区的引物，包括用于VHa，VHb、VHc、VHd、CH1、VL和CL区的引物)。这些引物可以用于扩增重或轻链可变区，所述重或轻链可变区随后可以分别插入载体例如ImmunoZAPTMH或ImmunoZAPTML(Stratagene)内。这些载体随后可以引入大肠杆菌、酵母、或基于哺乳动物的系统内用于表达。包含融合的VH和VL结构域的大量单链蛋白质可以使用这些方法产生(参见Bird等人，Science 242:423-426，1988)。
一旦产生根据本发明的抗体的细胞已使用任何上述免疫接种和其他技术获得，特异性抗体基因就可以根据如本文所述的标准操作通过由此分离和扩增DNA或mRNA进行克隆。由此产生的抗体可以进行测序并且鉴定的CDR和编码CDR的DNA可以如先前所述进行处理以产生根据本发明的其他抗体。
优选地结合剂与sclerostin特异性结合。如同所有结合剂和结合测定法一样，本领域技术人员应当理解结合剂不应与其可检测地结合以便在治疗上有效且合适的各种部分对于列举将是无穷尽和不实际的。因此，对于本文公开的结合剂，术语“特异性结合”指结合剂以比它与无关的对照蛋白质的结合更大的亲和力与sclerostin优选人sclerostin结合的能力。优选地对照蛋白质是鸡蛋蛋白溶菌酶。优选地结合剂与sclerostin结合的亲和力是与对照蛋白质的亲和力的至少50、100、250、500、1000或10,000倍。结合剂对于人sclerostin的亲和力可以小于或等于1x 10-7M、小于或等于1x 10-8M、小于或等于1x10-9M、小于或等于1x 10-10M、小于或等于1x 10-11M、或小于或等于1x 10-12M。
亲和力可以通过亲和力ELISA测定法进行测定。在某些实施方案中，亲和力可以通过BIAcore测定法进行测定。在某些实施方案中，亲和力可以通过动力学方法进行测定。在某些实施方案中，亲和力可以通过平衡/溶解法进行测定。此类方法在本文中进一步详细描述或是本领域已知的。
本发明的sclerostin结合剂优选在本文描述的基于细胞的测定法和/或本文描述的体内测定法中调节sclerostin功能，和/或与本文描述的一种或多种表位结合，和/或交叉阻断本申请中描述的抗体之一的结合，和/或被本申请中描述的抗体之一交叉阻断与sclerostin的结合。因此此类结合剂可以使用本文描述的测定法进行鉴定。
在某些实施方案中，结合剂通过首先鉴定抗体来产生，所述抗体在本文描述的基于细胞和/或体内测定法中与本文提供的一种或多种表位结合和/或中和，和/或交叉阻断本申请中描述的抗体，和/或被本申请中描述的抗体之一交叉阻断与sclerostin的结合。来自这些抗体的CDR区随后用于插入合适的生物相容性构架内以产生sclerostin结合剂。结合剂的非CDR部分可以由氨基酸组成，或可以是非蛋白质分子。本文描述的测定法允许表征结合剂。优选地本发明的结合剂是如本文定义的抗体。
本领域技术人员应当理解某些蛋白质例如抗体可以经历各种翻译后修饰。这些修饰的类型和程度通常取决于用于表达蛋白质的宿主细胞系以及培养条件。此类修饰可以包括糖基化、甲硫氨酸氧化、二酮哌嗪(diketopiperizine)形成、天冬氨酸异构化和天冬酰胺脱酰胺的变化。常见的修饰是由于羧肽酶的作用失去羧基末端碱性残基(例如赖氨酸或精氨酸)(如Harris，RJ.Journal of Chromatography705:129-134，1995中描述的)。
称为Ab-A、Ab-B、Ab-C、Ab-D和Ab-1的抗体在下文描述。“HC”指重链和“LC”指轻链。对于下文的某些抗体，CDR是带方框阴影的和恒定(C)区以粗体斜体显示。
Ab-D
抗体D(在本文中也称为Ab-D和Mab-D)是显示与sclerostin高亲和力结合的小鼠抗体。Ab-D的BIAcore结合模式显示于图18中。
成熟形式(信号肽被去除)的Ab-D轻链的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-D LC的核酸序列如下：
包括信号肽的Ab-D LC的氨基酸序列如下：
包括信号肽编码序列的Ab-D LC的核酸序列：
成熟形式(信号肽被去除)的Ab-D HC重链的氨基酸序列如下：
编码成熟形式(信号肽被去除)的Ab-D HC的核酸序列是：
包括信号肽的Ab-D HC的氨基酸序列是：
包括信号肽编码序列的Ab-D HC的核酸序列是：
Ab-D重链可变区中的CDR(互补决定区)序列如下：
CDR-H1:DHYMS(SEQ ID NO:39)
CDR-H2:DINPYSGETTYNQKFKG(SEQ ID NO:40)
CDR-H3:DDYDASPFAY(SEQ ID NO:41)
Ab-D轻链可变区中的CDR序列是：
CDR-L1:QASQGTSINLN(SEQ ID NO:42)
CDR-L2:GSSNLED(SEQ ID NO:43)
CDR-L3:LQHSYLPYT(SEQ ID NO:44)
Ab-C
抗体C(在本文中也称为Ab-C和Mab-C)是显示与sclerostin高亲和力结合的小鼠抗体。Ab-C的BIAcore结合模式显示于图17中。成熟形式(信号肽被去除)的Ab-C轻链的氨基酸序列如下：
编码成熟形式(信号肽被去除)的Ab-C LC的核酸序列是：
包括信号肽的Ab-C LC的氨基酸序列是：
包括信号肽编码序列的Ab-C LC的核酸序列是：
Ab-C重链
成熟形式(信号肽被去除)的Ab-C HC的氨基酸序列是：
编码成熟形式(信号肽被去除)的Ab-C HC的核酸序列如下：
包括信号肽的Ab-C HC的氨基酸序列是：
包括信号肽编码序列的Ab-C HC的核酸序列是：
Ab-C重链可变区中的CDR(互补决定区)序列如下：
CDR-H1:DCYMN(SEQ ID NO:45)
CDR-H2:DINPFNGGTTYNQKFKG(SEQ ID NO:46)
CDR-H3:SHYYFDGRVPWDAMDY(SEQ ID NO:47)
Ab-C轻链可变区的CDR序列是：
CDR-L1:KASQSVDYDGDSYMN(SEQ ID NO:48)
CDR-L2:AASNLES(SEQ ID NO:49)
CDR-L3:QQSNEDPWT(SEQ ID NO:50)
Ab-A
抗体A(在本文中也称为Ab-A和Mab-A)是显示与sclerostin高亲和力结合的兔-小鼠嵌合抗体。Ab-A的BIAcore结合模式显示于图15中。
Ab-A轻链
成熟形式(信号肽被去除)的Ab-A LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-A LC的核酸序列：
包括信号肽的Ab-A LC的氨基酸序列是：
包括信号肽编码序列的Ab-A LC的核酸序列是：
成熟形式(信号肽被去除)的Ab-A HC的氨基酸序列是：
编码成熟形式(信号肽被去除)的Ab-A HC的核酸序列：
包括信号肽的Ab-A HC的氨基酸序列是：
包括信号肽编码序列的Ab-A HC的核酸序列：
Ab-A重链可变区中的CDR(互补决定区)序列如下：
CDR-H1：SYWMN(SEQ ID NO：51)
CDR-H2：TIDSGGRTDYASWAKG(SEQ ID NO：52)
CDR-H3：NWNL(SEQ ID NO：53)
Ab-A轻链可变区的CDR序列是：
CDR-L1：QSSQSVYDNNWLA(SEQ ID NO：54)
CDR-L2：DASDLAS(SEQ ID NO：55)
CDR-L3：QGAYNDVIYA(SEQ ID NO：56)
Ab-A是人源化的，且称为抗体1(在本文中也称为Ab-1)具有下列序列：
包括信号肽编码序列的Ab-1 LC可变区的核酸序列是
ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCTCAAGTTCTGACCCAGAGTCCAAGCAGTCTCTCCGCCAGCGTAGGCGATCGTGTGACTATTACCTGTCAATCTAGTCAGAGCGTGTATGATAACAATTGGCTGGCGTGGTACCAGCAAAAACCGGGCAAAGCCCCGAAGCTGCTCATCTATGACGCGTCCGATCTGGCTAGCGGTGTGCCAAGCCGTTTCAGTGGCAGTGGCAGCGGTACTGACTTTACCCTCACAATTTCGTCTCTCCAGCCGGAAGATTTCGCCACTTACTATTGTCAAGGTGCTTACAACGATGTGATTTATGCCTTCGGTCAGGGCACTAAAGTAGAAATCAAACGT(SEQ ID NO：74)
包括信号肽的Ab-1 LC可变区的氨基酸序列是：
MDTRAPTQLLGLLLLWLPGATFAQVLTQSPSSLSASVGDRVTITCQSSQSVYDNNWLAWYQQKPGKAPKLLIYDASDLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQGAYNDVIYAFGQGTKVEIKR(SEQ ID NO：75)
包括信号肽编码序列的Ab-1 HC可变区的核酸序列是：
ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCACTGTGAGGTGCAGCTGTTGGAGTCTGGAGGCGGGCTTGTCCAGCCTGGAGGGAGCCTGCGTCTCTCTTGTGCAGCAAGCGGCTTCAGCTTATCCTCTTACTGGATGAATTGGGTGCGGCAGGCACCTGGGAAGGGCCTGGAGTGGGTGGGCACCATTGATTCCGGAGGCCGTACAGACTACGCGTCTTGGGCAAAGGGCCGTTTCACCATTTCCCGCGACAACTCCAAAAATACCATGTACCTCCAGATGAACTCTCTCCGCGCAGAGGACACAGCACGTTATTACTGTGCACGCAACTGGAATCTGTGGGGTCAAGGTACTCTTGTAACAGTCTCGAGC(SEQ ID NO：76)
包括信号肽的Ab-1 HC可变区的氨基酸序列
METGLRWLLLVAVLKGVHCEVQLLESGGGLVQPGGSLRLSCAASGFSLSSYWMNWVRQAPGKGLEWVGTIDSGGRTDYASWAKGRFTISRDNSKNTMYLQMNSLRAEDTARYYCARNWNLWGQGTLVTVSS(SEQ ID NO：77)
Ab-1重链可变区中的CDR(互补决定区)序列如下：
CDR-H1：SYWMN(SEQ ID NO：51)
CDR-H2：TIDSGGRTDYASWAKG(SEQ ID NO：52)
CDR-H3：NWNL(SEQ ID NO：53)
Ab-1轻链可变区的CDR序列是：
CDR-L1：QSSQSVYDNNWLA(SEQ ID NO：54)
CDR-L2：DASDLAS(SEQ ID NO：55)
CDR-L3：QGAYNDVIYA(SEQ ID NO：56)
Ab-B
抗体B(在本文中也称为Ab-B和Mab-B)是显示与sclerostin高亲和力结合的小鼠抗体。Ab-B的BIAcore结合模式显示于图16中。
Ab-B轻链
成熟形式(信号肽被去除)的Ab-B LC的氨基酸序列是：
编码成熟形式(信号肽被去除)的Ab-B LC的核酸序列是：
包括信号肽的Ab-B LC的氨基酸序列是：
包括信号肽编码序列的Ab-B LC的核酸序列是：
Ab-B重链
成熟形式(信号肽被去除)的Ab-B HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-B HC的核酸序列：
包括信号肽的Ab-B HC的氨基酸序列：
包括信号肽编码序列的Ab-B HC的核酸序列：
Ab-B重链可变区中的CDR(互补决定区)序列如下：
CDR-H1:TSGMGVG(SEQ ID NO:57)
CDR-H2:HIWWDDVKRYNPVLKS(SEQ ID NO:58)
CDR-H3:EDFDYDEEYYAMDY(SEQ ID NO:59)
Ab-B轻链可变区的CDR序列是：
CDR-L1:SASSSVSFVD(SEQ ID NO:60)
CDR-L2:RTSNLGF(SEQ ID NO:61)
CDR-L3:QQRSTYPPT(SEQ ID NO:62)
本文公开的抗体与对蛋白质的体内活性重要的人sclerostin区域结合。抗体与sclerostin的结合可以例如与通过在体内使用例如实施例5和9(小鼠)以及实施例12(猴)中所述的抗体达到的骨矿物质密度中的增加相关。骨形成、骨矿物质含量、骨量、骨质量和骨强度中的至少一种的增加也可以通过在体内使用例如实施例5和9(小鼠)以及实施例12(猴)中所述的抗体来达到。因为抗体与sclerostin的结合主要由其CDR序列来决定，所以用于实践本发明的抗体可以在合适构架中具有所有或某些公开的CDR序列来产生，其中所述抗体保留与sclerostin特异性结合的能力，且能够预期达到例如骨矿物质密度中的增加。此类抗体在人或动物病症的治疗中有用，所述病症由低骨形成、低骨矿物质密度、低骨矿物质含量、低骨量、低骨质量和低骨强度中的至少一种引起，与这些关联，或导致这些。构建和表达包含本发明的CDR的抗体及其片段的方法是本领域技术人员已知的。
因此在一个实施方案中本发明涉及分离的抗体包括Ab-A或其抗原结合片段，其与sclerostin特异性结合且其中重链可变结构域包含至少一个CDR，所述CDR具有SEQ ID NO:51中给出的关于CDR-H1的序列、关于CDR-H2的SEQ ID NO:52或关于CDR-H3的SEQ ID NO:53。抗体或其抗原结合片段可以包含重链可变结构域，其中CDR由关于CDR-H1的SEQ ID NO:51、关于CDR-H2的SEQ ID NO:52和关于CDR-H3的SEQ ID NO:53中的至少一种肽组成。
当在本发明的抗体中存在轻链时，轻链可以是任何合适的互补链且可以特别选自其中可变结构域包含至少一个CDR的轻链，所述CDR具有SEQ ID NO:54中给出的关于CDR-L1的序列、关于CDR-L2的SEQ ID NO:55或关于CDR-L3的SEQ ID NO:56。抗体或其抗原结合片段可以包含轻链可变结构域，其中CDR由关于CDR-L1的SEQ ID NO:54、关于CDR-L2的SEQ IDNO:55和关于CDR-L3的SEQ ID NO:56中的至少一种肽组成。
本发明进一步涉及分离的抗体包括Ab-B或其抗原结合片段，其与sclerostin特异性结合且其中重链可变结构域包含至少一个CDR，该CDR具有SEQ ID NO:57中给出的关于CDR-H1的序列、关于CDR-H2的SEQ ID NO:58或关于CDR-H3的SEQ ID NO:59。抗体或其抗原结合片段可以包含重链可变结构域，其中CDR由关于CDR-H1的SEQ ID NO:57、关于CDR-H2的SEQ ID NO:58和关于CDR-H3的SEQ ID NO:59中的至少一种肽组成。
当在本发明的抗体中存在轻链时，轻链可以是任何合适的互补链且可以特别选自其中可变结构域包含至少一个CDR的轻链，所述CDR具有SEQ ID NO:60中给出的关于CDR-L1的序列、关于CDR-L2的SEQ ID NO:61或关于CDR-L3的SEQ ID NO:62。抗体或其抗原结合片段可以包含轻链可变结构域，其中CDR由关于CDR-L1的SEQ ID NO:60、关于CDR-L2的SEQ IDNO:61和关于CDR-L3的SEQ ID NO:62中的至少一种肽组成。
本发明再进一步涉及分离的抗体包括Ab-C或其抗原结合片段，其与sclerostin特异性结合且其中重链可变结构域包含至少一个CDR，该CDR具有SEQ ID NO:45中给出的关于CDR-H1的序列、关于CDR-H2的SEQ ID NO:46或关于CDR-H3的SEQ ID NO:47。抗体或其抗原结合片段可以包含重链可变结构域，其中CDR由关于CDR-H1的SEQ ID NO:45、关于CDR-H2的SEQ ID NO:46和关于CDR-H3的SEQ ID NO:47中的至少一种肽组成。
当在本发明的抗体中存在轻链时，轻链可以是任何合适的互补链且可以特别选自其中可变结构域包含至少一个CDR的轻链，所述CDR具有SEQ ID NO:48中给出的关于CDR-L1的序列、关于CDR-L2的SEQ ID NO:49或关于CDR-L3的SEQ ID NO:50。抗体或其抗原结合片段可以包含轻链可变结构域，其中CDR由关于CDR-L1的SEQ ID NO:48、关于CDR-L2的SEQ IDNO:49和关于CDR-L3的SEQ ID NO:50中的至少一种肽组成。
本发明还涉及分离的抗体包括Ab-D或其抗原结合片段，其与sclerostin特异性结合且其中重链可变结构域包含至少一个CDR，该CDR具有SEQ ID NO:39中给出的关于CDR-H1的序列、关于CDR-H2的SEQ ID NO:40或关于CDR-H3的SEQ ID NO:41。抗体或其抗原结合片段可以包含重链可变结构域，其中CDR由关于CDR-H1的SEQ ID NO:39、关于CDR-H2的SEQ IDNO:40和关于CDR-H3的SEQ ID NO:41中的至少一种肽组成。
当在本发明的抗体中存在轻链时，轻链可以是任何合适的互补链且可以特别选自其中可变结构域包含至少一个CDR的轻链，所述CDR具有SEQ ID NO:42中给出的关于CDR-L1的序列、关于CDR-L2的SEQ ID NO:43或关于CDR-L3的SEQ ID NO:44。抗体或其抗原结合片段可以包含轻链可变结构域，其中CDR由关于CDR-L1的SEQ ID NO:42、关于CDR-L2的SEQ IDNO:43和关于CDR-L3的SEQ ID NO:44中的至少一种肽组成。
另外的抗sclerostin抗体在下文描述。对于某些氨基酸序列，互补决定区(CDR)是带方框阴影的和恒定区是粗体斜体。
Ab-2
抗体2(也称为Ab-2)的LC和HC序列如下：
Ab-2轻链:
成熟形式(信号肽被去除)的Ab-2 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-2 LC的核酸序列：
包括信号肽的Ab-2 LC的氨基酸序列：
包括信号肽编码序列的Ab-2 LC的核酸序列：
Ab-2重链
成熟形式(信号肽被去除)的Ab-2 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-2 HC的核酸序列：
包括信号肽的Ab-2 HC的氨基酸序列：
包括信号肽编码序列的Ab-2 HC的核酸序列：
Ab-3
抗体3(在本文中也称为Ab-3)的LC和HC序列如下：
Ab-3轻链
成熟形式(信号肽被去除)的Ab-3 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-3 LC的核酸序列：
包括信号肽的Ab-3 LC的氨基酸序列：
包括信号肽编码序列的Ab-3 LC的核酸序列：
Ab-3重链
成熟形式(信号肽被去除)的Ab-3 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-3 HC的核酸序列：
包括信号肽的Ab-3 HC的氨基酸序列：
包括信号肽编码序列的Ab-3 HC的核酸序列：
Ab-4
抗体4(在本文中也称为Ab-4)的LC和HC序列如下：
Ab-4轻链:
成熟形式(信号肽被去除)的Ab-4 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-4 LC的核酸序列：
包括信号肽的Ab-4 LC的氨基酸序列：
包括信号肽编码序列的Ab-4 LC的核酸序列：
Ab-4重链:
成熟形式(信号肽被去除)的Ab-4 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-4 HC的核酸序列：
包括信号肽的Ab-4 HC的氨基酸序列：
包括信号肽编码序列的Ab-4 HC的核酸序列：
Ab-4被人源化以产生Ab-5。
Ab-5
抗体5(在本文中也称为Ab-5)的LC和HC序列如下：
Ab-5轻链:
成熟形式(信号肽被去除)的Ab-5 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-5 LC的核酸序列：
包括信号肽的Ab-5 LC的氨基酸序列：
包括信号肽编码序列的Ab-5 LC的核酸序列：
Ab-5重链:
成熟形式(信号肽被去除)的Ab-5 HC的氨基酸序列：
不含羧基末端赖氨酸的成熟形式(信号肽被去除)的Ab-5 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-5 HC的核酸序列：
包括信号肽的Ab-5 HC的氨基酸序列：
包括信号肽编码序列的Ab-5 HC的核酸序列：
Ab-5可变结构域:
Ab-5轻链可变结构域的氨基酸序列(不含信号序列)：
Ab-5轻链可变结构域的DNA序列(不含信号序列)：
Ab-5重链可变结构域的氨基酸序列(不含信号序列)：
Ab-5重链可变结构域的DNA序列(不含信号序列)：
Ab-5重链可变区中的CDR(互补决定区)序列如下：
CDR-H1:DYNMH(SEQ ID NO:245)
CDR-H2:EINPNSGGAGYNQKFKG(SEQ ID NO:246)
CDR-H3:LGYDDIYDDWYFDV(SEQ ID NO:247)
Ab-5轻链可变区的CDR序列是：
CDR-L1:RASQDISNYLN(SEQ ID NO:78)
CDR-L2:YTSRLLS(SEQ ID NO:79)
CDR-L3:QQGDTLPYT(SEQ ID NO:80)
Ab-6
抗体6(在本文中也称为Ab-6)的LC和HC序列如下：
Ab-6轻链:
成熟形式(信号肽被去除)的Ab-6 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-6 LC的核酸序列：
包括信号肽的Ab-6 LC的氨基酸序列：
包括信号肽编码序列的Ab-6 LC的核酸序列：
Ab-6重链:
成熟形式(信号肽被去除)的Ab-6 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-6 HC的核酸序列：
包括信号肽的Ab-6 HC的氨基酸序列：
包括信号肽编码序列的Ab-6 HC的核酸序列：
Ab-7
抗体7(在本文中也称为Ab-7)的LC和HC序列如下：
Ab-7轻链:
成熟形式(信号肽被去除)的Ab-7 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-7 LC的核酸序列：
包括信号肽的Ab-7 LC的氨基酸序列：
包括信号肽编码序列的Ab-7 LC的核酸序列：
Ab-7重链:
成熟形式(信号肽被去除)的Ab-7 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-7 HC的核酸序列：
包括信号肽的Ab-7 HC的氨基酸序列：
包括信号肽编码序列的Ab-7 HC的核酸序列：
Ab-8
抗体8(在本文中也称为Ab-8)的LC和HC序列如下：
Ab-8轻链:
成熟形式(信号肽被去除)的Ab-8 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-8 LC的核酸序列：
包括信号肽的Ab-8 LC的氨基酸序列：
包括信号肽编码序列的Ab-8 LC的核酸序列：
Ab-8重链:
成熟形式(信号肽被去除)的Ab-8 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-8 HC的核酸序列：
包括信号肽的Ab-8 HC的氨基酸序列：
包括信号肽编码序列的Ab-8 HC的核酸序列：
Ab-9
抗体9(在本文中也称为Ab-9)的LC和HC序列如下：
Ab-9轻链:
成熟形式(信号肽被去除)的Ab-9 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-9 LC的核酸序列：
包括信号肽的Ab-9 LC的氨基酸序列：
包括信号肽编码序列的Ab-9 LC的核酸序列：
Ab-9重链：
成熟形式(信号肽被去除)的Ab-9 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-9 HC的核酸序列：
包括信号肽的Ab-9 HC的氨基酸序列：
包括信号肽编码序列的Ab-9 HC的核酸序列：
Ab-10
抗体10(在本文中也称为Ab-10)的LC和HC序列如下：
Ab-10轻链：
成熟形式(信号肽被去除)的Ab-10 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-10 LC的核酸序列：
包括信号肽的Ab-10 LC的氨基酸序列：
包括信号肽编码序列的Ab-10 LC的核酸序列：
Ab-10重链：
成熟形式(信号肽被去除)的Ab-10 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-10 HC的核酸序列：
包括信号肽的Ab-10 HC的氨基酸序列：
包括信号肽编码序列的Ab-10 HC的核酸序列：
Ab-11
抗体11(在本文中也称为Ab-11)的LC和HC序列如下：
Ab-11轻链：
成熟形式(信号肽被去除)的Ab-11 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-11 LC的核酸序列：
包括信号肽的Ab-11 LC的氨基酸序列：
包括信号肽编码序列的Ab-11 LC的核酸序列：
Ab-11重链：
成熟形式(信号肽被去除)的Ab-11 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-11 HC的核酸序列：
包括信号肽的Ab-11 HC的氨基酸序列：
包括信号肽编码序列的Ab-11 HC的核酸序列：
Ab-12
抗体12(在本文中也称为Ab-12)的LC和HC序列如下：
Ab-12轻链：
成熟形式(信号肽被去除)的Ab-12 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-12 LC的核酸序列：
包括信号肽的Ab-12 LC的氨基酸序列：
包括信号肽编码序列的Ab-12 LC的核酸序列：
Ab-12重链：
成熟形式(信号肽被去除)的Ab-12 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-12 HC的核酸序列：
包括信号肽的Ab-12 HC的氨基酸序列：
包括信号肽编码序列的Ab-12 HC的核酸序列：
Ab-13
抗体13(在本文中也称为Ab-13)的LC和HC序列如下：
Ab-13轻链：
成熟形式(信号肽被去除)的Ab-13 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-13 LC的核酸序列：
包括信号肽的Ab-13 LC的氨基酸序列：
包括信号肽编码序列的Ab-13 LC的核酸序列：
Ab-13重链：
成熟形式(信号肽被去除)的Ab-13 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-13 HC的核酸序列：
包括信号肽的Ab-13 HC的氨基酸序列：
包括信号肽编码序列的Ab-13 HC的核酸序列：
Ab-13被人源化以产生Ab-14。
抗体14(在本文中也称为Ab-14)的LC和HC序列如下：
Ab-14轻链：
成熟形式(信号肽被去除)的Ab-14 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-14 LC的核酸序列：
包括信号肽的Ab-14 LC的氨基酸序列：
包括信号肽编码序列的Ab-14 LC的核酸序列：
Ab-14重链：
成熟形式(信号肽被去除)的Ab-14 HC的氨基酸序列：
不含羧基末端赖氨酸的成熟形式(信号肽被去除)的Ab-14 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-14 HC的核酸序列：
包括信号肽的Ab-14 HC的氨基酸序列：
包括信号肽编码序列的Ab-14 HC的核酸序列：
Ab-14重链可变区中的CDR序列是：
CDR-H1:DYYMN(SEQ ID NO:296)
CDR-H2:DINPYNDDTTYNHKFKG(SEQ ID NO:297)
CDR-H3:ETAVITTNAMD(SEQ ID NO:298)
Ab-14轻链可变区的CDR序列是：
CDR-L1:RASSSVTSSYLN(SEQ ID NO:284)
CDR-L2:STSNLAS(SEQ ID NO:285)
CDR-L3:QQYDFFPST(SEQ ID NO:286)
Ab-14可变结构域:
Ab-14轻链可变结构域的氨基酸序列(不含信号序列)：
Ab-14轻链可变结构域的DNA序列(不含信号序列)：
Ab-14重链可变结构域的氨基酸序列(不含信号序列)：
Ab-14重链可变结构域的DNA序列(不含信号序列)：
Ab-3被人源化以产生Ab-15。
Ab-15
抗体15(在本文中也称为Ab-15)的LC和HC序列如下：
Ab-15轻链：
成熟形式(信号肽被去除)的Ab-15 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-15 LC的核酸序列：
包括信号肽的Ab-15 LC的氨基酸序列：
包括信号肽编码序列的Ab-15 LC的核酸序列：
Ab-15重链
成熟形式(信号肽被去除)的Ab-15 HC的氨基酸序列。
不含羧基末端赖氨酸的成熟形式(信号肽被去除)的Ab-15 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-15 HC的核酸序列：
包括信号肽的Ab-15 HC的氨基酸序列：
包括信号肽编码序列的Ab-15 HC的核酸序列：
Ab-15重链可变区中的CDR序列是：
CDR-H1:DFYLH(SEQ ID NO:290)
CDR-H2:RIDPENGDTLYDPKFQD(SEQ ID NO:291)
CDR-H3:EADYFHDGTSYWYFDV(SEQ ID NO:292)
Ab-15轻链可变区的CDR序列是：
CDR-L1:SVSSTISSNHLH(SEQ ID NO:278)
CDR-L2:GTSNLAS(SEQ ID NO:279)
CDR-L3:QQWSSYPLT(SEQ ID NO:280)
Ab-15可变结构域:
Ab-15轻链可变结构域的氨基酸序列(不含信号序列)：
Ab-15轻链可变结构域的DNA序列(不含信号序列)：
Ab-15重链可变结构域的氨基酸序列(不含信号序列)：
Ab-15重链可变结构域的DNA序列(不含信号序列)：
Ab-11被人源化以产生Ab-16。
Ab-16
抗体16(在本文中也称为Ab-16)的LC和HC序列如下：
Ab-16轻链：
成熟形式(信号肽被去除)的Ab-16LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-16 LC的核酸序列：
包括信号肽的Ab-16 LC的氨基酸序列：
包括信号肽编码序列的Ab-16 LC的核酸序列：
Ab-16重链：
成熟形式(信号肽被去除)的Ab-16 HC的氨基酸序列：
不含羧基末端赖氨酸的成熟形式(信号肽被去除)的Ab-16 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-16 HC的核酸序列：
包括信号肽的Ab-16 HC的氨基酸序列：
包括信号肽编码序列的Ab-16 HC的核酸序列：
Ab-16重链可变区中的CDR序列是：
CDR-H1:DYYIH(SEQ ID NO:293)
CDR-H2:RVDPDNGETEFAPKFPG(SEQ ID NO:294)
CDR-H3:EDYDGTYTWFPY(SEQ ID NO:295)
Ab-16轻链可变区的CDR序列是：
CDR-L1:RASSSISYIH(SEQ ID NO:281)
CDR-L2:ATSNLAS(SEQ ID NO:282)
CDR-L3:QQWSSDPLT(SEQ ID NO:283)
Ab-16可变结构域:
Ab-16轻链可变结构域的氨基酸序列(不含信号序列)：
Ab-16轻链可变结构域的DNA序列(不含信号序列)：
Ab-16重链可变结构域的氨基酸序列(不含信号序列)：
Ab-16重链可变结构域的DNA序列(不含信号序列)：
另外的抗体在本文中称为抗体17-22(在本文中也称为Ab-17、Ab-18、Ab-19、Ab-20、Ab-21和Ab-22)。关于Ab-17、Ab-19和Ab-21的所有VK区的κ恒定区如下：
TDAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC(SEQ ID NO：323)
关于Ab-17、Ab-19和Ab-21的所有VH区的重链恒定区如下：
AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK(SEQ ID NO：324)
在下列抗体氨基酸序列中，带方框阴影的氨基酸表示互补决定区(CDR)，有下划线的氨基酸表示信号肽。
Ab-17
包括信号肽的Ab-17 LC的氨基酸序列：
MDFQVQIFSFMLISVTVILSSGEIVLTQSPALMAASPGEKVTITCSVSSSISSSNLHWSQQKSGTSPKLWIYGTSNLASGVPVRFSGSGSGTSYSLTISSMEAEDAATYYCQQWTTTYTFGSGTKLELKR(SEQ ID NO：299)
包括信号肽的Ab-17 LC的核酸序列：
ATGGATTTTCAGGTGCAGATTTTCAGCTTCATGCTAATCAGTGTCACAGTCATATTGTCCAGTGGAGAAATTGTGCTCACCCAGTCTCCAGCACTCATGGCTGCATCTCCAGGGGAGAAGGTCACCATCACCTGCAGTGTCAGCTCGAGTATAAGTTCCAGCAACTTACACTGGTCCCAGCAGAAGTCAGGAACCTCCCCCAAACTCTGGATTTATGGCACATCCAACCTTGCTTCTGGAGTCCCTGTTCGCTTCAGTGGCAGTGGATCTGGGACCTCTTATTCTCTCACAATCAGCAGCATGGAGGCTGAAGATGCTGCCACTTATTACTGTCAACAGTGGACTACTACGTATACGTTCGGATCGGGGACCAAGCTGGAGCTGAAACGT(SEQ ID NO：300)
包括信号肽的Ab-17 HC的氨基酸序列：
MGWNWIIFFLMAVVTGVNSEVQLRQSGADLVKPGASVKLSCTASGFNIKDYYIHWVKQRPEQGLEWIGRIDPDNGESTYVPKFQGKATITADTSSNTAYLQLRSLTSEDTAIYYCGREGLDYGDYYAVDYWGQGTSVTVSS(SEQ ID NO：301)
包括信号肽的Ab-17 HC的核酸序列：
ATGGGATGGAACTGGATCATCTTCTTCCTGATGGCAGTGGTTACAGGGGTCAATTCAGAGGTGCAGTTGCGGCAGTCTGGGGCAGACCTTGTGAAGCCAGGGGCCTCAGTCAAGTTGTCCTGCACAGCTTCTGGCTTCAACATTAAAGACTACTATATACACTGGGTGAAGCAGAGGCCTGAACAGGGCCTGGAGTGGATTGGAAGGATTGATCCTGATAATGGTGAAAGTACATATGTCCCGAAGTTCCAGGGCAAGGCCACTATAACAGCAGACACATCATCCAACACAGCCTACCTACAACTCAGAAGCCTGACATCTGAGGACACTGCCATCTATTATTGTGGGAGAGAGGGGCTCGACTATGGTGACTACTATGCTGTGGACTACTGGGGTCAAGGAACCTCGGTCACAGTCTCGAGC(SEQ ID NO：302)
Ab-17被人源化以产生Ab-18。
Ab-18
包括信号肽的Ab-18 LC的氨基酸序列：
MDMRVPAQLLGLLLLWLPGARCDIQLTQSPSFLSASVGDRVTITCSVSSSISSSNLHWYQQKPGKAPKLLIYGTSNLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQWTTTYTFGQGTKLEIKR(SEQ ID NO：303)
包括信号肽的Ab-18 LC的核酸序列：
ATGGATATGCGCGTGCCGGCGCAGCTGCTGGGCCTGCTGCTGCTGTGGCTGCCGGGCGCGCGCTGCGATATTCAGCTGACCCAGAGCCCGAGCTTTCTGAGCGCGAGCGTGGGCGATCGCGTGACCATTACCTGCAGCGTGAGCAGCAGCATTAGCAGCAGCAACCTGCATTGGTATCAGCAGAAACCGGGCAAAGCGCCGAAACTGCTGATTTATGGCACCAGCAACCTGGCGAGCGGCGTGCCGAGCCGCTTTAGCGGCAGCGGCAGCGGCACCGAATTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTTGCGACCTATTATTGCCAGCAGTGGACCACCACCTATACCTTTGGCCAGGGCACCAAACTGGAAATTAAACGT(SEQ ID NO：304)
包括信号肽的Ab-18 HC的氨基酸序列：
MDWTWSILFLVAAPTGAHSEVQLVQSGAEVKKPGASVKVSCKASGFNIKDYYIHWVRQAPGQGLEWMGRIDPDNGESTYVPKFQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREGLDYGDYYAVDYWGQGTLVTVSS(SEQ ID NO：305)
包括信号肽的Ab-18 HC的核酸序列：
ATGGATTGGACCTGGAGCATTCTGTTTCTGGTGGCGGCGCCGACCGGCGCGCATAGCGAAGTGCAGCTGGTGCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGCGAGCGTGAAAGTGAGCTGCAAAGCGAGCGGCTTTAACATTAAAGATTATTATATTCATTGGGTGCGCCAGGCGCCGGGCCAGGGCCTGGAATGGATGGGCCGCATTGATCCGGATAACGGCGAAAGCACCTATGTGCCGAAATTTCAGGGCCGCGTGACCATGACCACCGATACCAGCACCAGCACCGCGTATATGGAACTGCGCAGCCTGCGCAGCGATGATACCGCGGTGTATTATTGCGCGCGCGAAGGCCTGGATTATGGCGATTATTATGCGGTGGATTATTGGGGCCAGGGCACCCTGGTGACCGTCTCGAGC(SEQ ID NO：306)
Ab-18轻链可变结构域的氨基酸序列(不含信号序列)：
DIQLTQSPSFLSASVGDRVTITCSVSSSISSSNLHWYQQKPGKAPKLLIYGTSNLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQWTTTYTFGQGTKLEIKR(SEQ ID NO：368)
Ab-18轻链可变结构域的DNA序列(不含信号序列)：
GATATTCAGCTGACCCAGAGCCCGAGCTTTCTGAGCGCGAGCGTGGGCGATCGCGTGACCATTACCTGCAGCGTGAGCAGCAGCATTAGCAGCAGCAACCTGCATTGGTATCAGCAGAAACCGGGCAAAGCGCCGAAACTGCTGATTTATGGCACCAGCAACCTGGCGAGCGGCGTGCCGAGCCGCTTTAGCGGCAGCGGCAGCGGCACCGAATTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTTGCGACCTATTATTGCCAGCAGTGGACCACCACCTATACCTTTGGCCAGGGCACCAAACTGGAAATTAAACGT(SEQ ID NO：369)
Ab-18重链可变结构域的氨基酸序列(不含信号序列)：
EVQLVQSGAEVKKPGASVKVSCKASGFNIKDYYIHWVRQAPGQGLEWMGRIDPDNGESTYVPKFQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREGLDYGDYYAVDYWGQGTLVTVSS(SEQ ID NO：370)
Ab-18重链可变结构域的DNA序列(不含信号序列)：
GAAGTGCAGCTGGTGCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGCGAGCGTGAAAGTGAGCTGCAAAGCGAGCGGCTITAACATTAAAGATTATTATATTCATTGGGTGCGCCAGGCGCCGGGCCAGGGCCTGGAATGGATGGGCCGCATTGATCCGGATAACGGCGAAAGCACCTATGTGCCGAAATTTCAGGGCCGCGTGACCATGACCACCGATACCAGCACCAGCACCGCGTATATGGAACTGCGCAGCCTGCGCAGCGATGATACCGCGGTGTATTATTGCGCGCGCGAAGGCCTGGATTATGGCGATTATTATGCGGTGGATTATTGGGGCCAGGGCACCCTGGTGACCGTCTCGAGC(SEQ ID NO：371)
Ab-19
包括信号肽的Ab-19LC的氨基酸序列：
MMSSAQFLGLLLLCFQGTRCDIQMTQTTSSLSASLGDRVNISCRASQDISSYLNWYQQKPDGTVKLLIYSTSRLNSGVPSRFSGSGSGTDYSLTISNLAQEDIATYFCQQDIKHPTFGGGTKLELKR(SEQ ID NO：307)
包括信号肽的Ab-19 LC的核酸序列：
ATGATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTTTTCAAGGTACCAGATGTGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCAACATCAGCTGCAGGGCAAGTCAGGACATTAGCAGTTATTTAAACTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCTGATCTACTCCACATCAAGATTAAACTCAGGAGTCCCATCAAGGTTCAGTGGCAGTGGGTCTGGGACAGATTATTCTCTCACTATTAGCAACCTGGCACAAGAAGATATTGCCACTTACTTTTGCCAACAGGATATTAAGCATCCGACGTTCGGTGGAGGCACCAAGTTGGAGCTGAAACGT(SEQID NO：308)
包括信号肽的Ab-19 HC的氨基酸序列：
MEWIWFLFLLSGTAGVHSEVQLQQSGPELVKPGASVKMSCKASGFTFTDYIMHWVKQKPGQGLEWIGYINPYNDDTEYNEKFKGKATLTSDKSSSTAYMDLSSLTSEGSAVYYCARSIYYYDAPFAYWGQGTLVTVSS(SEQ ID NO：309)
包括信号肽的Ab-19 HC的核酸序列：
ATGGAATGGATCTGGATATTTCTCTTCCTCCTGTCAGGAACTGCAGGTGTCCACTCTGAGGTCCAGCTGCAGCAGTCTGGACCTGAGCTGGTAAAGCCTGGGGCTTCAGTGAAGATGTCCTGCAAGGCTTCTGGGTTCACATTCACTGACTACATTATGCACTGGGTGAAGCAGAAGCCTGGGCAGGGCCTTGAGTGGATTGGATATATTAATCCTTACAATGATGATACTGAATACAATGAGAAGTTCAAAGGCAAGGCCACACTGACTTCAGACAAATCCTCCAGCACAGCCTACATGGATCTCAGCAGTCTGACCTCTGAGGGCTCTGCGGTCTATTACTGTGCAAGATCGATTTATTACTACGATGCCCCGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACAGTCTCGAGC(SEQ ID NO：310)
Ab-19被人源化以产生抗体20(在本文中也称为Ab-20)和抗体23(在本文中也称为Ab-23)。
Ab-20
IgG4形式
包括信号肽的Ab-20 LC的氨基酸序列：
MMSSAQFLGLLLLCFQGTRCDIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYSTSRLNSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQDIKHPTFGQGTKVEIKR(SEQ ID NO：311)
包括信号肽的Ab-20 LC的核酸序列：
ATGATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTTTTCAAGGTACCAGATGTGATATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGTGACCGTGTCACCATCACTTGCCGCGCAAGTCAGGATATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATTCTACTTCCCGTTTGAATAGTGGGGTCCCATCACGCTTCAGTGGCAGTGGCTCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGGATATTAAACACCCTACGTTCGGTCAAGGCACCAAGGTGGAGATCAAACGT(SEQID NO：312)
包括信号肽的Ab-20 HC的氨基酸序列：
MEWIWIFLFLLSGTAGVHSEVQLVQSGAEVKKPGSSVKVSCKASGFTFTDYIMHWVRQAPGQGLEWMGYINPYNDDTEYNEKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSIYYYDAPFAYWGQGTLVTVSS(SEQ ID NO：313)
包括信号肽的Ab-20 HC的核酸序列：
ATGGAATGGATCTGGATATTTCTCTTCCTCCTGTCAGGAACTGCAGGTGTCCACTCTGAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGTTTTACCTTCACCGACTATATTATGCACTGGGTGCGTCAGGCCCCTGGTCAAGGGCTTGAGTGGATGGGCTATATCAACCCTTATAATGATGACACCGAATACAACGAGAAGTTCAAGGGCCGTGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGCGCTCTGAGGACACGGCCGTGTATTACTGTGCGCGTTCGATTTATTACTACGATGCCCCGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACAGTCTCGAGC(SEQ ID NO：349)
Ab-23
IgG2形式
轻链：
成熟形式(信号肽被去除)的Ab-23 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-23 LC的核酸序列：
包括信号肽的Ab-23 LC的氨基酸序列：
包括信号肽编码序列的Ab-23 LC的核酸序列：
重链：
成熟形式(信号肽被去除)的Ab-23 HC的氨基酸序列：
不含羧基末端赖氨酸的成熟形式(信号肽被去除)的Ab-23 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-23 LC的核酸序列：
包括信号肽的Ab-23 HC的氨基酸序列：
包括信号肽编码序列的Ab-23 HC的核酸序列：
Ab-23重链可变区中的CDR(互补决定区)序列如下：
CDR-H1:DYIMH(SEQ ID NO:269)
CDR-H2:YINPYNDDTEYNEKFKG(SEQ ID NO:270)
CDR-H3:SIYYYDAPFAY(SEQ ID NO:271)
Ab-23轻链可变区的CDR序列是：
CDR-L1:RASQDISSYLN(SEQ ID NO:239)
CDR-L2:STSRLNS(SEQ ID NO:240)
CDR-L3:QQDIKHPT(SEQ ID NO:241)
Ab-23可变结构域：
Ab-23轻链可变结构域的氨基酸序列(不含信号序列)：
DIQMTQSPSS LSASVGDRVT ITCRASQDIS SYLNWYQQKP GKAPKLLIYS TSRLNSGVPSRFSGSGSGTD FTLTISSLQP EDFATYYCQQ DIKHPTFGQG TKVEIK(SEQ ID NO：364)
Ab-23轻链可变结构域的DNA序列(不含信号序列)：
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGTGACCGTGTC
ACC ATCACTTGCC GCGCAAGTCA GGATATTAGC AGCTATTTAAATTGGTATCA
GCAGAAACCA GGGAAAGCCC CTAAGCTCCT GATCTATTCTACTTCCCGTT
TGAATAGTGG GGTCCCATCA CGCTTCAGTG GCAGTGGCTCTGGGACAGAT
TTCACTCTCA CCATCAGCAG TCTGCAACCT GAAGATTTTGCAACTTACTA
CTGTCAACAG GATATTAAAC ACCCTACGTT CGGTCAAGGCACCAAGGTGG
AGATCAAA(SEQ ID NO：365)
Ab-23重链可变结构域的氨基酸序列(不含信号序列)：
EVQLVQSGAE VKKPGSSVKV SCKASGFTFT DYIMHWVRQA
PGQGLEWMGYINPYNDDTEY NEKFKGRVTI TADKSTSTAY MELSSLRSEDTAVYYCARSIYYYDAPFAYW GQGTLVTVSS(SEQ ID NO：366)
Ab-23重链可变结构域的DNA序列(不含信号序列)：
GAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAA
GGTC TCCTGCAAGG CTTCTGGTTT TACCTTCACC GACTATATTATGCACTGGGT
GCGTCAGGCC CCTGGTCAAG GGCTTGAGTG GATGGGCTATATCAACCCTT
ATAATGATGA CACCGAATAC AACGAGAAGT TCAAGGGCCGTGTCACGATT
ACCGCGGACA AATCCACGAG CACAGCCTAC ATGGAGCTGAGCAGCCTGCG
CTCTGAGGAC ACGGCCGTGT ATTACTGTGC GCGTTCGATTTATTACTACG
ATGCCCCGTT TGCTTACTGG GGCCAAGGGACTCTGGTCACCGTCTCTAGT(SEQ ID NO：367)
Ab-21
包括信号肽的Ab-21 LC的氨基酸序列：
MKSQTQVFVYMLLWLSGVEGDIVMTQSHKFMSTSVGDRVTITCKASQDVFTAVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSSYPLTFGAGTKLELKR(SEQ ID NO：315)
包括信号肽的Ab-21 LC的核酸序列：
ATGAAGTCACAGACCCAGGTCTTTGTATACATGTTGCTGTGGTTGTCTGGTGTTGAAGGAGACATTGTGATGACCCAGTCTCACAAATTCATGTCCACGTCAGTAGGAGACAGGGTCACCATCACCTGCAAGGCCAGTCAGGATGTCTTTACTGCTGTAGCCTGGTATCAACAGAAACCAGGACAATCTCCTAAACTACTGATTTACTGGGCATCCACCCGGCACACTGGAGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATTAGCAATGTGCAGTCTGAAGACTTGGCAGATTATTTCTGTCAACAATATAGCAGCTATCCTCTCACGTTCGGTGCTGGGACCAAGTTGGAGCTGAAACGT(SEQ ID NO：316)
包括信号肽的Ab-21 HC的氨基酸序列：
MGWNWIIFFLMAVVTGVNSEVQLQQSGAELVRPGALVKLSCKASGFNIKDYYMHWVKQRPEQGLEWIGRIDPENGDIIYDPKFQGKASITTDTSSNTAYLQLSSLTSEDTAVYYCAYDAGDPAWFTYWGQGTLVTVSS(SEQ ID NO：317)
包括信号肽的Ab-21 HC的核酸序列：
ATGGGATGGAACTGGATCATCTTCTTCCTGATGGCAGTGGTTACAGGGGTCAATTCAGAGGTTCAGCTGCAGCAGTCTGGGGCTGAGCTTGTGAGGCCAGGGGCCTTAGTCAAGTTGTCCTGCAAAGCTTCTGGCTTCAATATTAAAGACTACTATATGCACTGGGTGAAGCAGAGGCCTGAACAGGGCCTGGAGTGGATTGGAAGGATTGATCCTGAGAATGGTGATATTATATATGACCCGAAGTTCCAGGGCAAGGCCAGTATAACAACAGACACATCCTCCAACACAGCCTACCTGCAGCTCAGCAGCCTGACGTCTGAGGACACTGCCGTCTATTACTGTGCTTACGATGCTGGTGACCCCGCCTGGTTTACTTACTGGGGCCAAGGGACTCTGGTCACCGTCTCGAGC(SEQ ID NO：318)
Ab-21被人源化以产生Ab-22。
Ab-22
包括信号肽的Ab-22 LC的氨基酸序列：
MDMRVPAQLLGLLLLWLRGARCDIQMTQSPSSLSASVGDRVTITCKASQDVFTAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSSYPLTFGGGTKVEIKR(SEQ ID NO：319)
包括信号肽的Ab-22 LC的核酸序列：
ATGGATATGCGCGTGCCGGCGCAGCTGCTGGGCCTGCTGCTGCTGTGGCTGCGCGGCGCGCGCTGCGATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCGAGCGTGGGCGATCGCGTGACCATTACCTGCAAAGCGAGCCAGGATGTGTTTACCGCGGTGGCGTGGTATCAGCAGAAACCGGGCAAAGCGCCGAAACTGCTGATTTATTGGGCGAGCACCCGCCATACCGGCGTGCCGAGTCGCTTTAGCGGCAGCGGCAGCGGCACCGATTTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTTGCGACCTATTATTGCCAGCAGTATAGCAGCTATCCGCTGACCTTTGGCGGCGGCACCAAAGTGGAAATTAAACGT(SEQ ID NO：320)
包括信号肽的Ab-22 HC的氨基酸序列：
MDWTWSILFLVAAPTGAHSEVQLVQSGAEVKKPGASVKVSCKASGFNIKDYYMHWVRQAPGQGLEWIGRIDPENGDIIYDPKFQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAYDAGDPAWFTYWGQGTLVTVSS(SEQ ID NO：321)
包括信号肽的Ab-22 HC的核酸序列：
ATGGATTGGACCTGGAGCATTCTGTTTCTGGTGGCGGCGCCGACCGGCGCGCATAGCGAAGTGCAGCTGGTGCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGCGAGCGTGAAAGTGAGCTGCAAAGCGAGCGGCTTTAACATTAAAGATTATTATATGCATTGGGTGCGCCAGGCGCCGGGCCAGGGCCTGGAATGGATCGGCCGCATTGATCCGGAAAACGGCGATATTATTTATGATCCGAAATTTCAGGGCCGCGTGACCATGACCACCGATACCAGCACCAGCACCGCGTATATGGAACTGCGCAGCCTGCGCAGCGATGATACCGCGGTGTATTATTGCGCGTATGATGCGGGCGATCCGGCGTGGTTTACCTATTGGGGCCAGGGCACCCTGGTGACCGTCTCGAGC(SEQ ID NO：322)
Ab-22轻链可变结构域的氨基酸序列(不含信号序列)：
DIQMTQSPSS LSASVGDRVT ITCKASQDVF TAVAWYQQKP GKAPKLLIYW ASTRHTGVPSRFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSSYPLTFGG GTKVEIKR(SEQ ID NO：336)
Ab-22轻链可变结构域的DNA序列(不含信号序列)：
GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCGAGCGTGGGCGATCGCGTGACCATTACCTGCAAAGCGAGCCAGGATGTGTTTACCGCGGTGGCGTGGTATCAGCAGAAACCGGGCAAAGCGCCGAAACTGCTGATTTATTGGGCGAGCACCCGCCATACCGGCGTGCCGAGTCGCTTTAGCGGCAGCGGCAGCGGCACCGATTTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTTGCGACCTATTATTGCCAGCAGTATAGCAGCTATCCGCTGACCTTTGGCGGCGGCACCAAAGTGGAAATTAAACGT(SEQ ID NO：337)
Ab-22重链可变结构域的氨基酸序列(不含信号序列)：
EVQLVQSGAE VKKPGASVKV SCKASGFNIK DYYMHWVRQA
PGQGLEWIGRIDPENGDIIY DPKFQGRVTM TTDTSTSTAY MELRSLRSDD
TAVYYCAYDAGDPA WFTYWG QGTLVTVSS(SEQ ID NO：338)
Ab-22重链可变结构域的DNA序列(不含信号序列)：
GAAGTGCAGCTGGTGCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGCGAGCGTGAAAGTGAGCTGCAAAGCGAGCGGCTTTAACATTAAAGATTATTATATGCATTGGGTGCGCCAGGCGCCGGGCCAGGGCCTGGAATGGATCGGCCGCATTGATCCGGAAAACGGCGATATTATTTATGATCCGAAATTTCAGGGCCGCGTGACCATGACCACCGATACCAGCACCAGCACCGCGTATATGGAACTGCGCAGCCTGCGCAGCGATGATACCGCGGTGTATTATTGCGCGTATGATGCGGGCGATCCGGCGTGGTTTACCTATTGGGGCCAGGGCACCCTGGTGACCGTCTCGAGC(SEQ ID NO：339).
对于Ab-18、Ab-20和Ab-22，轻链人κ恒定区如下：
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*(SEQ ID NO：325)
并且重链人γ-4恒定区如下：
ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*(SEQ ID NO：326)
铰链区包含Ser-241-Pro突变以改善铰链稳定性(Angal S等人，(1993)，MolImmunol，30(1)，105-108)。
Ab-24
抗体24(在本文中也称为Ab-24)的LC和HC序列如下：
轻链：
成熟形式(信号肽被去除)的Ab-24 LC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-24 LC的核酸序列：
包括信号肽的Ab-24 LC的氨基酸序列：
包括信号肽编码序列的Ab-24 LC的核酸序列：
Ab-24重链：
成熟形式(信号肽被去除)的Ab-24 HC的氨基酸序列：
编码成熟形式(信号肽被去除)的Ab-24 HC的核酸序列：
包括信号肽的Ab-24 HC的氨基酸序列：
包括信号肽编码序列的Ab-24 HC的核酸序列：
Ab-24轻链可变区中的CDR序列如下：
CDR-L1：KASQSVDYDGTSYMN(SEQ ID NO:351)
CDR-L2：AASNLES(SEQ ID NO:352)
CDR-L3：QQSNEDPFT(SEQ ID NO:353)
Ab-24重链可变区中的CDR序列如下：
CDR-H1：TYWMN(SEQ ID NO:358)
CDR-H2：MIHPSASEIRLDQKFKD(SEQ ID NO:359)
CDR-H3：SGEWGSMDY(SEQ ID NO:360)
下表1提供了Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24的CDR的SEQ ID No和氨基酸序列。根据Kabat编号系统(Kabat等人，1987在Sequences of Proteins of Immunological Interest中，U.S.Department ofHealth and Human Services，NIH，USA)，L1、L2和L3指轻链CDR 1、2和3，并且H1、H2和H3指重链CDR1、2和3。
如果寡肽或多肽具有的氨基酸序列与上表1的CDR中的至少一种和/或下列sclerostin结合剂的CDR至少75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一，那么它在本发明的范围内：所述sclerostin结合剂交叉阻断抗体Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24中的至少一种与sclerostin的结合，和/或被抗体Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24中的至少一种交叉阻断与sclerostin的结合；和/或其中所述结合剂在基于细胞的矿化测定法中可以阻断sclerostin的抑制效应(即sclerostin中和结合剂)；和/或与Loop2表位结合的sclerostin结合剂；和/或与T20.6表位结合的sclerostin结合剂；和/或与“T20.6衍生物(胱氨酸结+4臂)”表位结合的sclerostin结合剂。
如果sclerostin结合剂多肽和抗体具有的氨基酸序列与抗体Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24中的至少一种的可变区至少85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一，且交叉阻断抗体Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24中的至少一种与sclerostin的结合，和/或被抗体Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24中的至少一种交叉阻断与sclerostin的结合；和/或在基于细胞的矿化测定法中可以阻断sclerostin的抑制效应(即sclerostin中和结合剂)；和/或与Loop2表位结合；和/或与T20.6表位结合；和/或与“T20.6衍生物(胱氨酸结+4臂)”表位结合，那么它们在本发明的范围内。
如果编码sclerostin结合剂的多核苷酸具有的多核苷酸序列与编码抗体Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24中的至少一种的可变区的多核苷酸至少85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％同一，且其中所编码的sclerostin结合剂交叉阻断抗体Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24中的至少一种与sclerostin的结合，和/或被抗体Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24中的至少一种交叉阻断与sclerostin的结合；和/或在基于细胞的矿化测定法中可以阻断sclerostin的抑制效应(即sclerostin中和结合剂)；和/或与Loop2表位结合；和/或与T20.6表位结合；和/或与“T20.6衍生物(胱氨酸结+4臂)”表位结合，那么它们在本发明的范围内。
根据本发明的抗体对人sclerostin的结合亲和力可以小于或等于1x 10-7M、小于或等于1x 10-8M、小于或等于1x 10-9M、小于或等于1x 10-10M、小于或等于1x 10-11M、或小于或等于1x 10-12M。
结合剂例如抗体或结合配偶体的亲和力以及结合剂(例如抗体)抑制结合的程度可以由本领域普通技术人员使用常规技术，例如Scatchard等人，(Ann.N.Y.Acad.Sci.51:660-672(1949))描述的那些或通过表面等离子共振(SPR；BIAcore，Biosensor，Piscataway，NJ)进行测定。对于表面等离子共振，靶分子被固定在固相上且暴露于沿着流动室流动的移动相中的配体。如果发生配体与固定靶的结合，那么局部折射率改变，导致SPR角度的变化，这可以通过检测反射光强度中的变化来实时监控。SPR信号变化速率可以进行分析以得到关于结合反应的结合和解离相的表观速率常数。这些值的比率产生表观平衡常数(亲和力)(参见，例如，Wolff等人，Cancer Res.53:2560-65(1993))。
根据本发明的抗体可以属于任何免疫球蛋白种类，例如IgG、IgE、IgM、IgD或IgA。它可以从动物获得或来源于动物，例如禽(例如，鸡)和哺乳动物，这包括但不限于小鼠、大鼠、仓鼠、兔或其他啮齿类动物、牛、马、绵羊、山羊、骆驼、人或其他灵长类动物。抗体可以是内在化抗体。抗体生产一般在美国专利公开号2004/0146888A1中公开。
表征测定法
在产生根据本发明的抗体的上述方法中，包括将特异性Ab-A、Ab-B、Ab-C、Ab-D、和抗体1-24(Ab-1至Ab-24)CDR操纵到新构架和/或恒定区内，合适的测定法可用于选择所需抗体或结合剂(即用于测定与sclerostin的结合亲和力的测定法；交叉阻断测定法；基于Biacore的“人sclerostin肽表位竞争结合测定法”；基于MC3T3-E1细胞的测定法；体内测定法)。
表位结合测定法
成熟形式的人sclerostin是具有胱氨酸结结构(图8和9)的190个氨基酸的糖蛋白。除胱氨酸结结构之外，蛋白质的特征为具有命名为Loop1、Loop2和Loop3的3个环。对人sclerostin实施蛋白水解消化以产生片段。简言之，使用不同蛋白酶，包括胰蛋白酶、aspN和lysC，产生具有各种切割位点和大小的片段。测定关于各种人sclerostin肽的序列和质量。评估抗体保护以确定对蛋白水解作用的易接受性的影响，包括修剪位点掩蔽和肽替换。最后，进行基于Biacore的“人sclerostin肽表位竞争结合测定法”。
sclerostin暴露于胰蛋白酶切割产生如图13中概括的肽片段模式。片段称为T19.2、T20、T20.6和T21-22。如图19B中示意性所示，T20.6表位是通过胱氨酸结区域的3个二硫键连接的4种分开的肽序列的复合物。2种肽通过2个二硫键连接。另外2种肽通过与前2种多肽示意性相交的1个二硫键连接。
通过胰蛋白酶消化产生的T20.6表位保留了天然多肽的胱氨酸结结构且由抗体Ab-C和Ab-D识别。表位T20.6的衍生物由胱氨酸结区域以及参考SEQ ID NO:1的序列位置中的氨基酸58-64、73-81、112-117和138-141组成。这种衍生表位显示于图21中。包含胱氨酸结区域的表位可以具有T20.6表位(图19B)中存在而T20.6衍生表位(图21)中不存在的一个或多个氨基酸。
另一种包含表位的区域在人sclerostin的Loop2区域(图19A)中鉴定，且由抗体Ab-A和Ab-B识别。Loop2表位包含SEQ ID NO:1的氨基酸86-111(C4GPARLLPNAIGRGKWWRPSGPDFRC5，SEQ ID NO:6)。在空间上，参考SEQ ID NO:1的全长sclerostin，包含Loop2的结构在一个末端由第86位的半胱氨酸(C4)和第144位的半胱氨酸(C8)之间的二硫键限定，且在另一个末端由第111位的半胱氨酸(C5)和第57位的半胱氨酸(C1)之间的二硫键限定。
通过aspN切割人sclerostin产生的肽显示于图12中。在该图中，这些肽命名为AspN14.6、AspN18.6和AspN22.7-23.5，且在本文中分别称为N14.6、N18.6和N22.7-23.5。
如通过基于Biacore的“人sclerostin肽表位竞争结合测定法”证明的，一组抗体显示与某些表位的特异性结合模式。简言之，抗体与待测试的表位一起预孵育，其浓度将使抗体上的表位结合位点饱和。抗体随后暴露于与芯片表面结合的sclerostin。合适的孵育和洗涤操作后，建立了竞争结合模式。如图18中所示，示例性抗体Ab-D与附着至芯片表面的sclerostin分子结合。抗体Ab-D与sclerostin的预孵育使抗体与芯片上的sclerostin的结合减少至接近于零。与由表位T19.2组成的肽一起预孵育显示T19.2不与sclerostin竞争结合抗体。然而，与命名为T20、T20.6、T21-22或N22.7-23.5的任何一种表位一起预孵育消除了抗体与芯片上的sclerostin的大部分结合。相反，抗体与命名为T19.2、N14.6或N18.6的任何一种表位一起预孵育并不消除抗体与sclerostin结合的能力。具有这种结合特征(图17)的第二种示例性抗体是Ab-C。
抗体Ab-D因此是与表位T20、T20.6、T21-22和N22.7-23.5结合的抗体组的示例和代表，且如通过阻断抗体与sclerostin结合的能力测量的，所述抗体组具有与表位T19.2、N14.6和N18.6的最低限度可检测的结合。具有这种特征性结合模式的抗体可以在抗体分子的一个或多个区域中共有或不共有氨基酸序列。抗体相似性例如通过与上述每种表位一起预孵育随后与sclerostin结合的能力在功能上测定。显示的结合模式类似于或等同于抗体Ab-D的那种的抗体包括在本发明中。“类似于”意指例如抗体将显示与多肽T20、T20.6、T21-22和N22.7-23.5中的每一种结合，由此这种结合将特异性竞争掉至少50％的抗体与sclerostin的结合，百分比是相对于结合将在不存在与sclerostin或sclerostin肽一起预孵育的情况下发生的结合而言。抗体还将显示与多肽T19.2、N14.6和N18.6很少或无法检测的结合，导致结合减少30％或更少，所述百分比是相对于在不存在与sclerostin或sclerostin肽一起预孵育的情况下发生的结合而言。
例如，不被具体机制束缚，图18的抗体结合模式暗示抗体Ab-D和具有Ab-D的表位结合模式的其他抗体与之结合的表位空间由包含sclerostin的胱氨酸结区域的多肽组成。
因此，如本文公开的和参考图19B，示例性T20.6表位包含经由3个分开的二硫键附着的4条肽链。肽链SAKPVTELVC3SGQC4GPAR(SEQ ID NO:3)通过从C3到C7以及从C4到C8的二硫键与肽链LVASC7KC8KRLTR(SEQ ID NO:5)附着。肽链DVSEYSC1RELHFTR(SEQ ID NO:2)通过从C1到C5的二硫键与肽链WWRPSGPDFRC5IPDRYR(SEQ ID NO:4)附着。如图19B中举例说明的，SEQ ID NO:3和5的多肽通过立体构造保持与SEQ ID NO:2和4的多肽结合，其中C1-C5键与C4-C8和C3-C7键的平面相交且位于其间。
如本文公开的和参考图21，T20.6的示例性衍生表位包含经由3个分开的二硫键附着的4条肽链。肽链SAKPVTELVC3SGQC4(SEQ ID NO:70)通过从C3到C7以及从C4到C8的二硫键与肽链LVASC7KC8(SEQ ID NO:71)附着。肽链C1RELHFTR(SEQ ID NO:72)通过从C1到C5的二硫键与肽链C5IPDRYR(SEQ ID NO:73)附着。如图21中举例说明的，SEQ ID NO:70和71的多肽通过立体构造保持与SEQ ID NO:72和73的多肽结合，其中C1-C5键与C4-C8和C3-C7键的平面相交且位于其间。
抗体Ab-A是第二种抗体组的示例和代表，所述抗体组具有的与人sclerostin肽的特征性结合模式不同于抗体Ab-C和Ab-D获得的那种。如通过阻断抗体与sclerostin结合的能力测量的(图15)，Ab-A以及它代表的抗体组与N22.7-23.5表位结合，且具有与表位T19.2、T20、T20.6、T21-22、N14.6或N18.6的最低限度可检测的结合。具有这种结合特征(图16)的第二种示例性抗体是Ab-B。具有这种特征性结合模式的抗体可以在抗体分子的一个或多个区域中共有或不共有氨基酸序列。抗体相似性例如通过与上述每种表位一起预孵育随后与sclerostin结合的能力在功能上测定。显示的结合模式类似于或等同于抗体Ab-A的那种的抗体包括在本发明中。“类似于”意指例如抗体将显示与N22.7-23.5多肽结合，由此这种结合将特异性竞争出至少50％的抗体与sclerostin的结合，所述50％是相对于在不存在与sclerostin或sclerostin肽一起预孵育的情况下发生的结合而言。抗体还将显示与多肽T19.2、T20、T20.6、T21-22、N14.6和N18.6很少或无法检测的结合，导致结合减少30％或更少，所述百分比是相对于在不存在与sclerostin或sclerostin肽一起预孵育的情况下发生的结合而言。
例如，不被具体机制束缚，图15的抗体结合模式暗示抗体Ab-A和具有Ab-A的表位结合模式的其他抗体与之结合的表位空间由包含sclerostin的Loop2区域的多肽组成。因此，如本文公开的和参考图19A，Loop2区域可以描述为线性肽，但当它存在于天然sclerostin或其中天然二硫键结构被维持的sclerostin的包含胱氨酸结的部分中时，它获得三级结构。如实施例中讨论的，Loop2表位的线性或三级结构可以影响抗体与其的结合。Loop2区域可以包含下列氨基酸序列：C4GPARLLPNAIGRGKWWRPSGPDFRC5(SEQ ID NO:6)。“C4”指位于参考SEQ ID NO:1的第86位的半胱氨酸残基。“C5”指位于参考SEQ ID NO:1的第111位的半胱氨酸残基。在天然sclerostin蛋白质中，C4通过二硫键与第144位(C8)的半胱氨酸连接，且C5通过二硫键与第57位(C1)的半胱氨酸连接。来源于Loop2区域的表位包括CGPARLLPNAIGRGKWWRPS(SEQ ID NO:63)；GPARLLPNAIGRGKWWRPSG(SEQ ID NO:64)；PARLLPNAIGRGKWWRPSGP(SEQ ID NO:65)；ARLLPNAIGRGKWWRPSGPD(SEQ ID NO:66)；RLLPNAIGRGKWWRPSGPDF(SEQ ID NO:67)；LLPNAIGRGKWWRPSGPDFR(SEQ ID NO:68)；和LPNAIGRGKWWRPSGPDFRC(SEQ ID NO:69)。
交叉阻断测定法
术语“交叉阻断”在本文中用于指抗体或其他结合剂干扰其他抗体或结合剂与sclerostin结合的能力。
抗体或其他结合剂能够干扰另一种抗体与sclerostin的结合，且因此它是否可以说成根据本发明的交叉阻断的程度可以使用竞争结合测定法来测定。一种特别合适的定量测定法使用Biacore机器，所述Biacore机器可以使用表面等离子共振技术测量相互作用的程度。另一种合适的定量交叉阻断测定法使用基于ELISA的方法以测量抗体或其他结合剂之间就其与sclerostin结合而言的竞争。
BIACORE交叉阻断测定法
下文一般描述了用于测定抗体或其他结合剂是否根据本发明交叉阻断或能够交叉阻断的合适Biacore测定法。为了方便起见对2种抗体进行了描述，但应当理解该测定法可以使用本文描述的任何sclerostin结合剂。Biacore机器(例如Biacore 3000)按照制造商的建议进行操作。
因此在一种交叉阻断测定法中，sclerostin使用标准胺偶联化学与CM5Biacore芯片偶联以产生sclerostin包被表面。一般地200-800共振单位的sclerostin将与芯片偶联(将产生可容易检测水平的结合但通过使用的测试试剂浓度可容易饱和的量)。
待评估其互相交叉阻断能力的2种抗体(称为A*和B*)以1比1摩尔比的结合位点在合适缓冲液中混合以制备测试混合物。当在结合位点的基础上计算浓度时，抗体的分子量假定为抗体的总分子量除以那种抗体上的sclerostin结合位点数目。
测试混合物中每种抗体的浓度应当足够高以容易地饱和Biacore芯片上捕获的sclerostin分子的那种抗体的结合位点。混合物中的抗体为相同的摩尔浓度(在结合的基础上)且那种浓度一般将为1.00－1.5微摩尔(在结合位点的基础上)。
同时制备包含单独的抗体A*和单独的抗体B*的分开溶液。这些溶液中的抗体A*和抗体B*应当在相同缓冲液中且应当是与测试混合物中一样的浓度。
测试混合物流经sclerostin包被的Biacore芯片且记录结合的总量。芯片随后以这样的方式处理以便去除结合的抗体而不损害芯片结合的sclerostin。一般地这通过用30mM HCl处理芯片60秒来完成。
单独的抗体A*溶液随后流经sclerostin包被的表面且记录结合的总量。芯片再次进行处理以去除所有结合的抗体而不损害芯片结合的sclerostin。
单独的抗体B*溶液随后流经sclerostin包被的表面且记录结合的总量。
接下来计算抗体A*和抗体B*的混合物的最大理论结合，且是每种抗体单独流经sclerostin表面时的结合的总和。如果实际记录的混合物的结合小于这个理论最大值，那么2种抗体互相交叉阻断。
因此，一般而言，根据本发明的交叉阻断抗体或其他结合剂在上述Biacore交叉阻断测定法中将与sclerostin结合，从而使得在测定法过程中以及本发明的第二种抗体或其他结合剂的存在下，记录的结合为最大理论结合的80％－0.1％(例如80％－4％)，特别是最大理论结合的75％－0.1％(例如75％－4％)，且更特别是2种抗体或结合剂组合的最大理论结合(正如上文定义的)的70％－0.1％(例如70％－4％)。
上述Biacore测定法是用于确定抗体或其他结合剂是否根据本发明互相交叉阻断的主要测定法。在罕见的情况下，特定抗体或其他结合剂可以不与经由胺化学与CM5Biacore芯片偶联的sclerostin结合(这通常在sclerostin上的相关结合位点经由与芯片的偶联被掩蔽或破坏时发生)。在此类情况下交叉阻断可以使用标记形式的Sclerostin测定，例如N末端His标记的Sclerostin(R&D Systems，Minneapolis，MN，USA；2005目录#1406-ST-025)。在这种特殊形式下，抗His抗体将与Biacore芯片偶联，随后His标记的Sclerostin将流经芯片表面且被抗His抗体捕获。交叉阻断分析将基本上如上所述进行，除了每个芯片再生循环后，新的His标记的sclerostin将装载回抗His抗体包被的表面上之外。除了给出的使用N末端His标记的Sclerostin例子之外，可替代地可以使用C末端His标记的sclerostin。此外，本领域已知的各种其他标记和标记结合蛋白组合可以用于此类交叉阻断分析(例如HA标记与抗HA抗体；FLAG标记与抗FLAG抗体；生物素标记与链霉亲和素)。
基于ELISA的交叉阻断测定法
下文一般描述了用于测定抗sclerostin抗体或其他sclerostin结合剂是否根据本发明交叉阻断或能够交叉阻断的ELISA测定法。为了方便起见，对2种抗体进行描述(Ab-X和Ab-Y)，但应当理解该测定法可以使用本文描述的任何sclerostin结合剂。
该测定法的一般原理是使抗sclerostin抗体包被在ELISA板的孔上。在溶液中加入(即，不与ELISA板结合)过量的第二种可能交叉阻断的抗sclerostin抗体。随后向孔中加入有限量的sclerostin。包被的抗体和溶液中的抗体竞争结合有限量的sclerostin分子。板随后进行洗涤以去除未被包被抗体结合的sclerostin，且同时去除第二种溶液相抗体以及第二种溶液相抗体和sclerostin之间形成的任何复合物。结合的sclerostin的量随后使用合适的sclerostin检测试剂进行测量。能够交叉阻断包被抗体的溶液中抗体将能够引起包被抗体可以结合的sclerostin分子的数目相对于在不存在第二种溶液相抗体的情况下包被抗体可以结合的sclerostin分子数目减少。
这种测定法在下文对于Ab-X和Ab-Y更进一步地详细描述。在其中Ab-X选择为固定抗体的情况下，它包被在ELISA板的孔上，这之后板用合适的封闭溶液封闭以最小化随后加入的试剂的非特异性结合。随后向ELISA板中加入过量Ab-Y，从而使得每孔的Ab-Xsclerostin结合位点摩尔量比ELISA板包被过程中每孔使用的Ab-X sclerostin结合位点摩尔量至少高10倍。随后加入sclerostin从而使得每孔加入的sclerostin摩尔量比用于包被每个孔的Ab-X sclerostin结合位点的摩尔量低至少25倍。合适的孵育期后，ELISA板进行洗涤且加入sclerostin检测试剂，以测量经由包被的抗sclerostin抗体(在这种情况下是Ab-X)特异性结合的sclerostin量。关于该测定法的背景信号定义为在含包被抗体(在这种情况下是Ab-X)、第二种溶液相抗体(在这种情况下是Ab-Y)、只有sclerostin缓冲液(即没有sclerostin)和sclerostin检测试剂的孔中获得的信号。关于该测定法的阳性对照信号定义为在含包被抗体(在这种情况下是Ab-X)、只有第二种溶液相抗体缓冲液(即没有第二种溶液相抗体)、sclerostin和sclerostin检测试剂的孔中获得的信号。ELISA测定法必须以这样的方式进行，以便使阳性对照信号是背景信号的至少6倍。
为了避免由何种抗体用作包被抗体和何种用作第二种(竞争者)抗体的选择产生的任何假象(例如，Ab-X和Ab-Y之间对于sclerostin的显著不同的亲和力)，交叉阻断测定法必须以2种形式进行：
1)形式1是其中Ab-X是包被在EILSA板上的抗体并且Ab-Y是在溶液中的竞争者抗体
和
2)形式2是其中Ab-Y是包被在EILSA板上的抗体并且Ab-X是在溶液中的竞争者抗体。
如果在形式1或形式2中，与在不存在溶液相抗sclerostin抗体的情况下(即阳性对照孔)获得的sclerostin检测信号比较，溶液相抗sclerostin抗体能够引起sclerostin检测信号(即由包被抗体结合的sclerostin量)减少60％－100％、特别是70％－100％、且更特别是80％－100％，那么Ab-X和Ab-Y被定义为交叉阻断的。
此类基于ELISA的交叉阻断测定法的例子可以在实施例7(“基于ELISA的交叉阻断测定法”)中找到。
基于细胞的中和测定法
培养的成骨细胞谱系细胞(原代细胞或细胞系)的矿化用作骨形成的体外模型。从经由一种或多种分化试剂诱导的成骨细胞谱系细胞分化开始，矿化需要约1至6周的时间发生。整个系列事件涉及细胞增殖、分化、细胞外基质产生、基质成熟和最终矿物质沉积，所述矿物质沉积指磷酸钙结晶化和/或沉积。以细胞增殖和分化开始、且以矿物质沉积结束的这种系列事件在本文中称为矿化。钙(矿物质)的测量是测定法的结果。
MC3T3-E1细胞(Sudo H，Kodama H-A，Amagai Y，Yamamoto S，Kasai S.1983.Invitro differentiation and calcification in a new clonal osteogenic cell linederived from newborn mouse calvaria.J.Cell Biol.96:191-198)和原始细胞系的亚克隆在分化试剂的存在下生长后可以在培养中形成矿物质。此类亚克隆包括MC3T3-E1-BF(Smith E，Redman R，Logg C，Coetzee G，Kasahara N，Frenkel B.2000.Glucocorticoidsinhibit developmental stage-specific osteoblast cell cycle.J.Biol.Chem.275:19992-20001)。对于MC3T3-E1-BF亚克隆以及原始MC3T3-E1细胞，sclerostin可以抑制逐渐导致且包括矿物质沉积的系列事件中的一个或多个(即sclerostin抑制矿化)。能够中和sclerostin抑制活性的抗sclerostin抗体允许培养物在sclerostin的存在下矿化，从而使得与只有sclerostin(即无抗体)的处理组中测量的钙量比较，磷酸钙(作为钙测量)沉积中存在统计上显著的增加。在显示于图22、23和24中的基于细胞的矿化测定法实验中使用的抗体具有约145Kd的分子量且每个抗体分子具有2个sclerostin结合位点。
当为了测定特定抗sclerostin抗体或抗sclerostin结合剂是否可以中和sclerostin(即，是sclerostin中和抗体或其衍生物，或是sclerostin中和结合剂)的目的进行该测定法时，该测定法中使用的sclerostin量必须是与没有sclerostin组中测量的钙量比较，引起只有sclerostin组中的磷酸钙(作为钙测量)沉积至少70％、统计上显著减少的sclerostin最小量。抗sclerostin中和抗体或抗sclerostin中和结合剂定义为与只有sclerostin(即没有抗体、没有结合剂)的处理组中测量的钙量比较，引起磷酸钙(作为钙测量)沉积中统计上显著的增加的那些。为了确定抗sclerostin抗体或抗sclerostin结合剂是否是中和性的，测定法中使用的抗sclerostin抗体或抗sclerostin结合剂的量必须是这样的，使得与每孔的sclerostin摩尔数目比较，存在过量的每孔的sclerostin结合位点摩尔量。取决于抗体效力，可能需要的过量倍数可以是24、18、12、6、3或1.5，并且本领域技术人员熟悉测试超过一种结合剂浓度的常规实践。例如非常有效的抗sclerostin中和抗体或抗sclerostin中和结合剂将能够中和sclerostin，即使当与每孔的sclerostin摩尔数目比较，每孔存在少于6倍过量的sclerostin结合位点摩尔量时。效力较少的抗sclerostin中和抗体或抗sclerostin中和结合剂将只在12、18或24倍过量时才能够中和sclerostin。这种效力全范围内的sclerostin结合剂适合作为中和性sclerostin结合剂。示例性基于细胞的矿化测定法在实施例8中详细描述。
可以中和人sclerostin的抗sclerostin抗体及其衍生物，以及可以中和人sclerostin的sclerostin结合剂可能在人病症/病症治疗中有用，所述病症/病症由低骨形成、低骨矿物质密度、低骨矿物质含量、低骨量、低骨质量和低骨强度中的至少一种引起，与这些关联，或导致这些。
体内中和测定法
与刺激新骨形成关联、或由刺激新骨形成产生的各种参数中的增加可以作为来自sclerostin结合剂体内测试的输出结果进行测量，以便鉴定能够中和sclerostin且因此能够引起新骨形成的刺激的那些结合剂。此类参数包括骨形成、骨矿物质密度、骨矿物质含量、骨量、骨质量和骨强度的各种血清合成代谢标记[例如，骨钙蛋白、P1NP(1型前胶原的n末端前肽)]，组织形态学标记(例如成骨细胞表面/骨表面；成骨速度/骨表面；小梁厚度)。sclerostin中和结合剂定义为与媒介物处理的动物比较，能够引起与刺激新骨形成关联、或由刺激新骨形成产生的任何参数中的统计上显著增加。此类体内测试可以在任何合适的哺乳动物(例如小鼠、大鼠、猴)中进行。此类体内测试的例子可以在实施例5(“抗sclerostin单克隆抗体的体内测试”)中找到。
尽管sclerostin的氨基酸序列在哺乳动物种类中并非100％等同(例如小鼠sclerostin与人sclerostin并非100％等同)，但本领域技术人员应当理解可以在体内中和某一物种(例如小鼠)的sclerostin且还能够在体外结合人sclerostin的sclerostin结合剂非常可能在体内中和人sclerostin。因此，此类人sclerostin结合剂(例如抗人sclerostin抗体)可能在人病症/病症治疗中有用，所述病症/病症由低骨形成、低骨矿物质密度、低骨矿物质含量、低骨量、低骨质量和低骨强度中的至少一种引起，与这些关联，或导致这些。其中同源重组已用于删除小鼠sclerostin基因且在其位置中插入人sclerostin基因的小鼠(即人sclerostin基因敲入(knock-in)小鼠或人SOST敲入小鼠)可以是另外的体内系统的例子。
提供了包含上述结合剂之一连同药学或生理学可接受载体、赋形剂或稀释剂的药物组合物，所述结合剂例如为针对人sclerostin的抗体Ab-A，Ab-B、Ab-C、Ab-D和Ab-1至Ab-24中的至少一种。药物组合物和治疗方法在于2004年6月16日提交的共同未决的申请序列号10/868,497中公开，所述申请要求序列号60/478,977的优先权，所述2个申请引入本文作为参考。
用于在各种治疗方案中使用本文所述药物组合物的合适剂量和治疗方案的开发是本领域众所周知的，所述治疗方案包括例如皮下、口服、肠胃外、静脉内、鼻内和肌内施用和配制，为了举例说明的一般目的其中一些在下文简要讨论。
在某些应用中，本文公开的药物组合物可以经由口部施用递送给动物。像这样，这些组合物可以与惰性稀释剂或与可同化的可食用载体一起配制，或它们可以封装在硬或软壳明胶胶囊中，或它们可以压制成片剂，或它们可以直接掺入饮食的食物中。
在某些情况下，将希望皮下、肠胃外、静脉内、肌内或甚至腹膜内递送本文公开的药物组合物。此类方法是本领域技术人员众所周知的，其中一些在例如美国专利号5,543,158；美国专利号5,641,515和美国专利号5,399,363中进一步描述。在某些实施方案中，作为游离碱或药理学可接受盐的活性化合物溶液可以在水中适当地与表面活性剂例如羟丙基纤维素混合进行制备。分散系也可以在丙三醇、液体聚乙二醇、及其混合物中以及在油中进行制备。在普通的贮存和使用条件下，这些制剂一般将包含防腐剂以预防微生物生长。
适合于注射用途的举例说明性药物形式包括无菌水溶液或分散系和用于临时制备无菌注射液或分散系的无菌粉末(例如，参见美国专利号5,466,468)。在所有情况下剂型必须是无菌的且必须流动至容易注射的程度。它在制备和贮存条件下必须是稳定的且必须针对微生物例如细菌和真菌的污染活动进行保护。载体可以是包含例如水、乙醇、多元醇(例如丙三醇、丙二醇和液体聚乙二醇等)、其合适混合物和/或植物油的溶剂或分散介质。合适的流动性可以例如通过使用包衣例如卵磷脂、在分散系的情况下通过维持所需颗粒大小和/或通过使用表面活性剂来维持。微生物活动的预防可以通过各种抗菌剂和抗真菌剂得到促进，例如对羟苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等。在许多情况下，将优选包括等渗剂，例如糖或氯化钠。可注射组合物的延长吸收可以通过在组合物中使用吸收延迟剂例如单硬脂酸铝和明胶来达到。
在一个实施方案中，对于在水溶液中的肠胃外施用，必要时溶液应当是适当缓冲的且液体稀释剂首先用足够的盐或葡萄糖变得等渗。这些特别的水溶液特别适合于静脉内、肌内、皮下和腹膜内施用。在这方面，可以使用的无菌水介质按照本公开内容对于本领域技术人员将是已知的。例如，一个剂量可以溶解于1ml等渗NaCl溶液中且加入1000ml皮下输液中或在计划的输注位点处进行注射，(参见例如Remington's PharmaceuticalSciences，第15版，第1035-1038和1570-1580页)。取决于待治疗受试者的病症，剂量中的某些变化将必然发生。此外，对于人施用，制剂当然将优选满足如FDA生物制品标准办公室(FDA Office of Biologics standards)要求的无菌、致热原性以及一般的安全性和纯度标准。
在本发明的另一实施方案中，本文公开的组合物可以以中性或盐形式进行配制。举例说明性药学可接受的盐包括酸加成盐(由蛋白质的游离氨基形成)以及由无机酸例如盐酸或磷酸形成的盐，或由此类有机酸如乙酸、草酸、酒石酸、扁桃酸等形成的盐。由游离羧基形成的盐还可以来源于无机碱，例如氢氧化钠、钾、铵、钙、或铁，以及此类有机碱如异丙胺、三甲胺、组氨酸、普鲁卡因等。配制后，溶液将以与剂量制剂相容的方式和治疗有效的量进行施用。
载体可以进一步包含任何和所有溶剂、分散介质、媒介物、包衣、稀释剂、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂、缓冲液、载体溶液、悬浮液、胶体等。用于药学活性物质的此类介质和试剂的使用是本领域众所周知的。除非任何常规介质或试剂与活性成分不相容，否则考虑其在治疗组合物中的使用。其它活性成分也可以掺入组合物中。短语“药学可接受的”指当给人施用时不会产生过敏或类似不利反应的分子实体和组合物。
在某些实施方案中，脂质体、纳米胶囊、微粒、脂质颗粒、囊泡等用于将本发明的组合物引入合适的宿主细胞/生物内。特别地，本发明的组合物可以封装在脂质颗粒、脂质体、囊泡、纳米球体、或纳米颗粒等中配制用于递送。可替代地，本发明的组合物可以与此类载体媒介物的表面共价或非共价地结合。
作为有效药物载体的脂质体和脂质体样制剂的形成和使用是本领域技术人员普遍知道的(参见例如Lasic，Trends Biotechnol.16(7):307-21，1998；Takakura，NipponRinsho 56(3):691-95，1998；Chandran等人，Indian J.Exp.Biol.35(8):801-09，1997；Margalit，Crit.Rev.Ther.Drug Carrier Syst.12(2-3):233-61，1995；美国专利号5,567,434；美国专利号5,552,157；美国专利号5,565,213；美国专利号5,738,868和美国专利号5,795,587，所述参考文献各自特别整体引入本文作为参考)。脂质体的使用在全身递送后似乎不会产生自身免疫应答或无法接受的毒性。在某些实施方案中，脂质体由磷脂形成，所述磷脂分散在水介质中且自发形成多层同心双层囊泡(也称为多层囊泡(MLV))。
可替代地，在其他实施方案中，本发明提供了本发明组合物的药学可接受的纳米胶囊制剂。纳米胶囊一般以稳定和可重复的方式封装化合物(参见，例如Quintanar-Guerrero等人，Drug Dev.Ind.Pharm.24(12):1113-28，1998)。为了避免由于细胞内聚合超载的副作用，此类超微粒(大小约0.1μm)可以使用能够在体内降解的聚合物进行设计。此类颗粒可以如例如Couvreur等人，Crit.Rev.Ther.Drug Carrier Syst.5(1):1-20，1988；zurMuhlen等人，Eur.J.Pharm.Biopharm.45(2):149-55，1998；Zambaux等人，J.ControlledRelease 50(1-3):31-40，1998；和美国专利号5,145,684所述进行制备。
另外，本发明的药物组合物可以连同包装材料一起置于容器内，所述包装材料提供关于此类药物组合物使用的说明书。一般地，此类说明书将包括描述试剂浓度，以及在某些实施方案内对重构药物组合物可能必需的赋形剂成分或稀释剂(例如，水、盐水或PBS)的相对量的实体表达。
施用的剂量可以是0.01mg/kg－100mg/kg体重。如对于本领域技术人员将是显而易见的，施用的量和频率当然将取决于此类因素如待治疗适应症的性质和严重度、所需应答、患者条件等。一般地，组合物可以通过如上所述的各种技术来施用。
骨矿物质含量和/或骨矿物质密度中的增加可以通过使用X射线(例如双能X射线骨吸收测量仪(Dual Energy X-ray Absorptometry)或“DEXA”)来直接测定，或通过测量下列来推断：1)骨形成和/或成骨细胞活性标记，例如但不限于成骨细胞特异性碱性磷酸酶、骨钙蛋白、1型前胶原羧基端前肽(PICP)、总碱性磷酸酶(参见Comier，Curr.Opin.inRheu.7:243(1995))和血清前胶原1N末端前肽(P1NP)和/或2)骨再吸收和/或破骨细胞活性标记，包括但不限于吡啶啉、脱氧吡啶啉、N端肽(N-telopeptide)、尿羟脯氨酸、血浆耐酒石酸盐酸性磷酸酶、和半乳糖基羟赖氨酸；(参见Comier，同上)、血清TRAP 5b(耐酒石酸盐酸性磷酸酶同型异构体5b)和血清交联C端肽(sCTXI)。骨量的量还可以由体重或通过使用其他方法来计算(参见Guinness-Hey，Metab.Bone Dis.Relat.Res.5:177-181，1984)。动物和特定动物模型在本领域中用于测试本发明的组合物和方法对例如骨丢失、骨再吸收、骨形成、骨强度或骨矿化的参数的影响，这模拟人疾病例如骨质疏松症和骨量减少的病症。此类模型的例子包括卵巢切除的大鼠模型(Kalu，D.N.，The ovariectomized rat model ofpostmenopausal bone loss.Bone and Mineral 15:175-192(1991)；Frost，H.M.和Jee，W.S.S.On the rat model of human osteopenias and osteoporosis.Bone and Mineral18:227-236(1992)；以及Jee，W.S.S.和Yao，W.，Overview：animal models of osteopeniaand osteoporosis.J.Musculoskel.Neuron.Interact.1:193-207(2001))。
可以通过本发明的组合物治疗的具体病症包括其中骨生长或发育异常的发育不良，以及广泛多样病因的骨量减少、骨质疏松症和骨丢失。此类病症的代表性例子包括软骨发育不全，颅骨锁骨发育不良，内生软骨瘤病，纤维性结构不良，高歇病，低磷酸盐血症佝偻病，马方综合征，mulliple hereditary exotoses，神经纤维瘤病，成骨不全，骨硬化症，全身脆弱性骨硬化，硬化损伤，假关节，化脓性骨髓炎，牙周病，抗癫痫药诱导的骨丢失，原发性和继发性甲状旁腺功能亢进症，家族性甲状旁腺功能亢进综合征，失重诱导的骨丢失，男性中的骨质疏松症，绝经后的骨丢失，骨关节炎，肾病性佝偻病，骨浸润性病症，口部骨丢失，颌骨坏死，青少年佩吉特病，肢骨纹状肥厚，代谢性骨病，肥大细胞增多症，镰状细胞性贫血/病，器官移植相关性骨丢失，肾移植相关性骨丢失，全身性红斑狼疮，强直性脊柱炎，癫痫，青少年关节炎，地中海贫血，粘多糖贮积病，法布里病，特纳综合征，唐氏综合征，克兰费尔特综合征，麻风病，佩特兹病，青少年特发性脊柱侧凸，婴儿期发作性多系统炎性疾病，温彻斯特综合征(Winchester Syndrome)，门克斯病，威尔逊病，局部缺血性骨病(例如累-卡-佩病、局限性游走性骨质疏松)，贫血状态，由类固醇引起的病症，糖皮质激素诱导的骨丢失，肝素诱导的骨丢失，骨髓病症，坏血病，营养不良，钙缺乏，特发性骨量减少或骨质疏松症，先天性骨量减少或骨质疏松，酒精中毒，慢性肝病，绝经后状态，慢性炎性病症，类风湿性关节炎，炎性肠病，溃疡性结肠炎，炎性结肠炎，克罗恩病，月经过少，无月经，妊娠，糖尿病，甲状腺功能亢进，甲状腺病症，甲状旁腺病症，库欣病，肢端肥大症，性腺机能减退(hypogonadism)，制动或废用，反射交感性营养不良综合征，局限性骨质疏松，骨软化症，与关节置换术相关的骨丢失，HIV相关的骨丢失，与生长激素缺少相关的骨丢失，与囊性纤维化相关的骨丢失，纤维性结构不良，化学治疗相关性骨丢失，肿瘤诱导的骨丢失，癌症相关的骨丢失，激素消融性骨丢失，多发性骨髓瘤，药物诱导的骨丢失，神经性厌食症，疾病相关的面骨丢失，疾病相关的颅骨丢失，疾病相关的颌骨丢失，疾病相关的头盖骨丢失，以及与太空旅行相关的骨丢失。进一步的病症涉及与衰老相关的骨丢失，包括与衰老相关的面骨丢失，与衰老相关的颅骨丢失，与衰老相关的颌骨丢失，以及与衰老相关的头盖骨丢失。
本发明的组合物还可以用于改善矫形术，牙科手术，植入手术，关节置换术，骨移植术，骨美容手术和骨修复例如骨折愈合、骨不连愈合(nonunion healing)、延迟的连接愈合和面部重建中的结果。一种或多种组合物可以在操作、置换、移植、手术或修复之前、之时和/或之后施用。
本发明还提供了包含根据本发明的至少一种抗sclerostin结合剂的诊断试剂盒。结合剂可以是抗体。此外，此类试剂盒可以任选包含下列中的一种或多种：
(1)关于使用一种或多种结合剂用于筛选、诊断、预后、治疗监控或这些应用的任何组合的说明书；
(2)针对抗sclerostin结合剂的标记的结合配偶体；
(3)在其上固定抗sclerostin结合剂的固相(例如反应条带)；和
(4)标明管理机构批准用于筛选、诊断、预后或治疗用途或其任何组合的标签或插页(insert)。
如果没有提供针对结合剂的标记的结合配偶体，那么结合剂自身可以用一种或多种可检测标记物进行标记，所述可检测标记物例如化学发光、酶、荧光、或放射性部分。
为了举例说明而不是为了限制提供下列实施例。
实施例
实施例1
Sclerostin的重组表达
重组人sclerostin/SOST从R&D Systems(Minneapolis，MN，USA；2006目录#1406-ST-025)商购可得。另外，重组小鼠sclerostin/SOST从R&D Systems(Minneapolis，MN，USA；2006目录#1589-ST-025)商购可得。
可替代地，不同种类的sclerostin可以在适应无血清悬浮培养的293T或293EBNA细胞中瞬时表达。转染可以作为500mL或1L培养物进行。下列试剂和材料可从Gibco BRL(现在是Invitrogen，Carlsbad，CA)获得。目录号在括号中列出：无血清DMEM(21068-028)；DMEM/F12(3:1)(21068/11765)；1X胰岛素-转铁蛋白-硒补充剂(51500-056)；1X Pen StrepGlut(10378-016)；2mM l-谷氨酰胺(25030-081)；20mM HEPES(15630-080)；0.01％Pluronic F68(24040-032)。简言之，细胞接种物(5.0-10.0X 105细胞/mL X培养物体积)在2,500RPM下于4℃离心10分钟以去除条件化培养基。
将细胞重悬浮于无血清DMEM中且再次在2,500RPM下于4℃离心10分钟。吸出洗涤溶液后，将细胞重悬浮于1L或3L转瓶培养中的生长培养基[DMEM/F12(3:1)+1X胰岛素-转铁蛋白-硒补充剂+1X Pen Strep Glut+2mM L-谷氨酰胺+20mM HEPES+0.01％Pluronic F68]中。转瓶培养在磁搅动板上维持在125RPM，所述磁搅动板置于维持在37℃和5％CO2的增湿孵育箱中。包含sclerostin的完整编码区(和终止密码子)与正好在起始位点ATG 5’的Kozak一致序列(例如CCACC)的哺乳动物表达质粒DNA(例如pcDNA3.1，pCEP4，InvitrogenLife Technologies，Carlsbad，CA)在50mL圆锥形管中与转染试剂混合。
DNA转染试剂复合物可以在无血清DMEM或OPTI-MEM以5-10％最终培养物体积制备。可以用于这个用途的转染试剂包括X-tremeGene RO-1539(Roche Applied Science，Indianapolis，IN)，FuGene6(Roche Applied Science，Indianapolis，IN)，Lipofectamine2000(Invitrogen，Carlsbad，CA)和293fectin(Invitrogen，Carlsbad，CA)。首先向无血清DMEM中加入1-5μg质粒DNA/mL培养物，随后为1-5μl转染试剂/mL培养物。复合物于室温孵育大约10－30分钟且随后加入转瓶中的细胞。转染/表达可以进行4－7天，这之后通过在4,000RPM下于4℃离心60分钟收获条件化培养基(CM)。
实施例2
重组sclerostin的纯化
重组sclerostin如下从哺乳动物宿主细胞中纯化。所有纯化过程在室温下进行。一种纯化方案用于纯化各种种类的sclerostin，包括鼠类和人sclerostin。该纯化方案使用亲和色谱法随后为阳离子交换色谱法。
肝素色谱法
哺乳动物宿主细胞条件化培养基(CM)在Beckman J6-M1离心机中在4000rpm下于4℃离心1小时以去除细胞碎片。CM上清液随后通过无菌的0.2μm过滤器进行过滤。(在这点上无菌过滤的CM可以任选冷冻贮存直至纯化。)如果CM被冷冻，那么它在下列温度或其组合下解冻：4℃、室温或温水。解冻后CM通过无菌的0.2μm过滤器进行过滤，且任选通过切向流超滤(TFF)使用10kD分子量截止膜进行浓缩。CM浓缩物通过无菌的0.2μm过滤器进行过滤，且随后装载到在PBS中平衡的肝素高性能(肝素HP)柱(GE Healthcare，前身为AmershamBiosciences)上。可替代地，过滤的CM上清液可以直接装载到在PBS中平衡的肝素HP柱上。
装载后，肝素HP柱用PBS洗涤直至流出物(flow-through)在280nm处的吸光度回到基线(即在装载CM上清液前测量的吸光度)。sclerostin随后使用溶于PBS的150mM－2M氯化钠线性梯度从柱中洗脱。监控洗出液在280nm处的吸光度并收集包含蛋白质的级分。级分随后通过考马斯染色的SDS-PAGE测定，以鉴定包含以糖基化sclerostin的大小移动的多肽的级分。来自柱的合适级分被合并以制备肝素HP库。
阳离子交换色谱法
从肝素HP柱中洗脱的sclerostin通过阳离子交换色谱法使用SP高性能(SPHP)层析介质(GE Healthcare，前身为Amersham Biosciences)进一步纯化。肝素HP库通过透析使用10,000MWCO膜(Pierce Slide-A-Lyzer)缓冲液更换到PBS内。透析的肝素HP库随后装载到在PBS中平衡的SPHP柱上。装载后，柱随后用PBS洗涤直至流出物在280nm处的吸光度回到基线。sclerostin随后使用溶于PBS的150mM－1M氯化钠线性梯度从SPHP柱中洗脱。监控洗出液在280nm处的吸光度并收集在级分中的洗脱的sclerostin。级分随后通过考马斯染色的SDS-PAGE测定，以鉴定包含以糖基化sclerostin的大小移动的多肽的级分。来自柱的合适级分被合并以制备SPHP库。
配制
纯化后，SPHP库通过透析使用10,000MWCO膜(Pierce Slide-A-Lyzer)在PBS中进行配制。如果sclerostin的浓缩是必需的，那么使用含10,000MWCO膜的离心装置(AmiconCentricon或Centriprep)。配制后sclerostin通过无菌的0.2μm过滤器进行过滤并贮存于4℃或冷冻。
实施例3
肽结合ELISA
一系列重叠肽(每种肽长度为大约20－25个氨基酸)基于大鼠sclerostin的已知氨基酸序列(SEQ ID NO:98)合成。肽这样设计使得它们全都包含还原的半胱氨酸残基；在其序列中未包含半胱氨酸的每种肽的C末端包括附加的半胱氨酸。这使得肽能够通过共价偶联使用商购可得的巯基结合板(Costar)以1μg/ml的浓度在包含1mM EDTA的磷酸盐缓冲盐水(PBS：pH 6.5)中与测定板结合。于室温孵育1小时后，板用包含0.5％吐温20的PBS洗涤3次。板通过与包含0.5％鱼皮明胶(Sigma)的PBS溶液一起孵育于室温封闭30分钟，且随后在包含0.5％吐温20的PBS中洗涤3次。
待测试抗体在包含0.5％鱼皮明胶的PBS中稀释至1μg/ml且与肽包被的板一起于室温孵育1小时。过量抗体通过用PBS和0.5％吐温20洗涤3次来去除。板随后与合适的二抗一起孵育，所述二抗与辣根过氧化物酶缀合(在包含0.5％吐温20的PBS中适当稀释)且能够与目的抗体结合。板随后洗涤3次：一次用包含0.5％吐温20的PBS，2次用PBS。最后板与辣根过氧化物酶显色底物(TMB-Stable Stop，RDI)一起于室温孵育5分钟，用酸来终止显色，且在450nm处测量板的光密度。
材料
Costar的巯基结合板(VWR#29442-278)
包被缓冲液：1XPBS PH 6.5+1mM EDTA
封闭缓冲液：1X PBS+0.5％鱼皮明胶(PBS来自CS；FSG来自Sigma#G 7765)
洗涤缓冲液：1X PBS+0.5％吐温20
大鼠Sclerostin肽
抗体样品：瞬时Ab，纯化的重组Ab，兔血清等。
合适的二抗：山羊抗兔/小鼠-HRP(Jackson Immuno Research,115-036-072)
TMB-Stable Stop(RDI#RDI-TMBSX-1L)
0.5M HCl
方法如下：
1.用100μl/孔、在1XPBS PH 6.5+1mM EDTA中稀释为1μg/ml的大鼠sclerostin肽包被板。使板于室温孵育1小时。(板应在打开后30分钟内使用)。
2.用洗涤缓冲液将板洗涤3次。
3.用200ul/孔封闭缓冲液将板封闭。使板于室温孵育30分钟。
4.如(2)中所述重复洗涤。
5.使板与50ul/孔在封闭缓冲液中稀释的样品一起孵育－血清滴度从1:100开始；使用纯的瞬时重组的Ab；使用1μg/ml纯化的重组Ab(所有样品一式两份地进行)。使板于室温孵育1小时。
6.如(2)中所述洗涤板。
7.使板与50ul/孔在封闭缓冲液中1:1600稀释的合适二抗(HRP标记的)一起孵育。使板于室温孵育1小时。
8.板用洗涤缓冲液洗涤1次，PBS洗涤2次。
9.使板与50μl/孔TMB一起于室温孵育5分钟。
10.用50μl/孔0.5M HCl终止反应。
11.在450nm波长处读板。
如上所述筛选下列肽序列：
QGWQAFKNDATEIIPGLREYPEPP(SEQ ID NO：82)
TEIIPGLREYPEPPQELENN(SEQ ID NO：83)
PEPPQELENNQTMNRAENGG(SEQ ID NO：84)
ENGGRPPHHPYDTKDVSEYS(SEQ ID NO：85)
CRELHYTRFVTDGP(SEQ ID NO：86)
CRELHYTRFVTDGPSRSAKPVTELV(SEQ ID NO：87)
CRSAKPVTELVSSGQSGPRARLL(SEQ ID NO：88)
CGPARLLPNAIGRVKWWRPNGPDFR(SEQ ID NO：89)
RAQRVQLLCPGGAAPRSRKV(SEQ ID NO：90)
PGGAAPRSRKVRLVAS(SEQ ID NO：91)
KRLTRFHNQSELKDFGPETARPQ(SEQ ID NO：92)
IPDRYAQRVQLLSPGG(SEQ ID NO：93)
SELKDFGPETARPQKGRKPRPRAR(SEQ ID NO：94)
KGRKPRPRARGAKANQAELENAY(SEQ ID NO：95)
PNAIGRVKWWRPNGPDFR(SEQ ID NO：96)
KWWRPNGPDFRCIPDRYRAQRV(SEQ ID NO：97).
高亲和力中和抗体(Ab-19)与2种重叠的肽序列结合：PNAIGRVKWWRPNGPDFR(SEQID NO：96)和KWWRPNGPDFRCIPDRYRAQRV(SEQ ID NO：97)。
这种操作允许识别与表观线性表位反应的抗体的表位。包含所有或部分抗体结合位点的肽将结合抗体且因此被检测。
实施例4
人sclerostin表位的鉴定
Sclerostin结构
成熟形式(信号肽被去除)的人sclerostin是190个氨基酸的蛋白质(图8)。图9显示了具有N末端臂(从N末端Q到半胱氨酸1)和C末端臂(从半胱氨酸8到末端Y)的sclerostin一般结构示意图。夹在这2个臂之间的是胱氨酸结结构和命名为Loop1、Loop2和Loop3的3个环。sclerostin中的4个二硫键是序列第57位的Cys1与序列第111位的Cys5连接(称为C1-C5)，序列第71位的Cys2与序列第125位的Cys6连接(称为C2-C6)，序列第82位的Cys3与序列第142位的Cys7连接(称为C3-C7)，序列第86位的Cys4与序列第144位的Cys8连接(称为C4-C8)。8员的环结构经由C3-C7和C4-C8二硫键形成。这种环结构连同穿过环的C1-C5二硫键一起形成一般的胱氨酸结。不是胱氨酸结部分的C2-C6使2个大环结构－Loop1(残基57－82)和Loop3(残基111－142)靠近。Loop2是从C4(残基86)到C5(残基111)。
实验
用于表征由抗sclerostin单克隆抗体结合的表位的一般方法涉及用不同蛋白酶使人sclerostin变成肽片段，测定各种人sclerostin肽的序列，分离这些肽，并使用基于Biacore的“人sclerostin肽表位竞争结合测定法”测试每种肽与特定单克隆抗体结合的能力。所得到的数据允许定位待测定的结合表位。
对肽消化物实施HPLC肽作图；收集单个峰，且通过基质辅助激光解吸质谱法(MALDI-MS)和电喷射离子化LC-MS(ESI-LC-MS)分析和/或通过N末端测序鉴定肽并作图。关于这些研究的所有HPLC分析使用反相C8柱(直径2.1mm x长度15cm)进行。HPLC肽作图使用0.05％三氟乙酸(移动相A)－在0.05％三氟乙酸中的90％乙腈的线性梯度进行。柱以0.2ml/分钟的流速经过50分钟运行。
胰蛋白酶和AspN内切蛋白酶消化
成熟形式的人sclerostin用在精氨酸和赖氨酸后切割的胰蛋白酶或AspN消化。约200μg sclerostin以0.5-1.0mg/ml与8μg胰蛋白酶或AspN一起在PBS(pH 7.2)中于37℃孵育20小时。
胰蛋白酶消化
胰蛋白酶消化物的HPLC色谱法产生几个主峰(图10A)。序列分析对胰蛋白酶消化后由HPLC回收的肽峰进行。同时进行肽消化物的在线ESI LC-MS分析以确定由HPLC分开的肽的精确质量。肽峰中存在的肽的身份因此得到确定(图11)。图13显示各种肽序列(T19.2、T20、T20.6、T21-22)与sclerostin序列的比对。每个T后的数字(例如T19.2)反映保留时间。T19.2包含通过C2-C6二硫键连接的2种肽(一种来自Loop1和一种来自Loop3)。T20包含通过胱氨酸结结构结合在一起的2种肽，其中完整的Loop1和3通过C2-C6二硫键结合在一起，而大部分Loop2不存在。T20.6包含通过胱氨酸结结构结合在一起的4种序列，但缺失部分Loop1和3(T19.2部分)且缺失大部分Loop2。T21-22几乎等同于T20但在Loop2区域中具有3个额外氨基酸。
AspN消化
AspN消化物的HPLC色谱法产生几个主峰(图10B)。序列分析对由HPLC回收的肽峰进行。同时进行肽消化物的在线ESI LC-MS分析以确定由HPLC分开的肽的精确质量。来自AspN消化的肽峰中存在的肽的身份因此得到确定(图12)。图14显示各种肽序列(AspN14.6、AspN18.6、AspN22.7-23.5)与sclerostin序列的比对。每个AspN后的数字(例如AspN18.6)反映保留时间。AspN14.6包含来自sclerostin的N和C末端臂的3种短肽，而AspN18.6是来自sclerostin的N末端臂的较大肽。AspN22.7-23.5包含104个氨基酸的单一肽片段，其包含所有8个半胱氨酸(4个二硫键)、胱氨酸结以及所有Loop1、2和3。
用于表征表位的策略是使用这些各种胰蛋白酶和AspN产生的人sclerostin肽，且确定哪些肽仍能由各种抗体(Ab-A、Ab-B、Ab-C和Ab-D)结合。特别地这在基于Biacore的“人sclerostin肽表位竞争结合测定法”中进行测试，其中特定单克隆抗体与固定在Biacore芯片上的人sclerostin的结合在各种分离的胰蛋白酶和AspN HPLC肽级分中的每一种存在或不存在的情况下进行测定。在不存在任何竞争肽的情况下，特定单克隆抗体能够结合在芯片上的人sclerostin且产生共振单位RU应答。特定单克隆抗体与溶液中的完整人sclerostin一起预孵育，随后测试与芯片的结合，表明Mab与溶液中的人sclerostin结合阻止Mab与芯片上的人sclerostin结合，从而证实了这种竞争测定法的一般原理是可靠的。
这种一般操作对于每种肽个体进行重复。获得的强RU应答表明测试的特定肽不能结合溶液中的Mab(从而Mab自由结合已固定在芯片上的人sclerostin)。相反，强RU应答的缺失表明Mab能够结合溶液中的sclerostin肽。这些结合模式与各种sclerostin肽的已知身份结合，用于确定由抗sclerostin抗体Ab-A、Ab-B、Ab-C和Ab-D结合的sclerostin表位。
基于Biacore的人sclerostin肽表位竞争结合测定法
人sclerostin表面的制备：
成熟形式的人sclerostin与BIAcore传感器芯片(CM5)表面的固定根据制造商的说明书进行。简言之，传感器芯片表面上的羧基通过注射60μL包含0.2M N-乙基-N’-(二甲氨基丙基)碳二亚胺(EDC)和0.05M N-羟基琥珀酰亚胺(NHS)的混合物被活化。人sclerostin在10mM乙酸钠，pH 4.0中稀释为20μg/mL的浓度，随后在活化的CM5表面上注射。表面上的过量反应基团通过注射60μL 1M乙醇胺来灭活。最终固定水平对于人sclerostin表面是～5000共振单位(RU)。同时在传感器芯片上制备空白、模拟偶联的参考表面。
结合特异性分析：
不含氯化钙或氯化镁的1X磷酸盐缓冲盐水来自Gibco/Invitrogen，Carlsbad，CA。无IgG的牛血清白蛋白级分V来自Sigma-Aldrich，St.Louis，MO。每种Mab(2nM)在注射在固定的人sclerostin表面上之前在样品缓冲液(1X PBS+0.005％P-20+0.1mg/mL BSA)中分别与20nM人sclerostin或特定人sclerostin肽(注：在AspN14.6中有3种未连接的肽)一起孵育。关于注射进样的流速为5μL/分钟，随后为使用在8mM甘氨酸，pH 2.0中的1M NaCl以30μL/分钟进行30秒的表面再生。数据使用BIAevaluation 3.2进行分析，且呈现于图15(Ab-A)、图16(Ab-B)、图17(Ab-C)和图18(Ab-D)中。
Loop2和T20.6表位:
关于2种代表性抗体(Ab-A和Ab-B)的sclerostin肽结合模式基本上是相同的(图15和图16)且显示这2种抗体都只能结合AspN22.7-23.5肽。AspN22.7-23.5与所有其他sclerostin肽之间的唯一差别是AspN22.7-23.5包含完整的Loop2。这显示Ab-A和Ab-B结合sclerostin的Loop2区域从而定义了Loop2表位(图19A)。关于Ab-C和Ab-D的sclerostin肽结合模式基本上是彼此相同的(图17和图18)，但完全不同于对于Ab-A和Ab-B发现的那种。在这个实施例中测试的肽中，Ab-C和Ab-D可以与之结合的最小型肽是T20.6肽。这个结果定义了T20.6表位(图19B)。
蛋白酶保护测定法：
这个测定法的一般原理是Mab与sclerostin的结合可以导致某些特异性蛋白酶切割位点的保护且这种信息可以用于确定Mab与之结合的sclerostin区域。
“T20.6衍生物1(胱氨酸结+4臂)”表位:
图20显示关于人sclerostin Ab-D复合物(图20A：人sclerostin以1:1的摩尔比与Ab-D一起预孵育，然后如上所述用胰蛋白酶消化)和单独的人sclerostin的HPLC肽图(图20B：人sclerostin如上所述用胰蛋白酶消化)。与图20B比较，图20A中的T19.2和T20.6肽峰显示其各自峰高中的明显减少。峰高中的这种减少伴随肽T20和T21-22峰高中的增加。这些数据表明Loop1和Loop3中的碱性氨基酸残基(在不存在Ab-D的情况下经由胰蛋白酶切割产生肽T19.2和T20.6)当Ab-D与sclerostin预结合时对经由胰蛋白酶的切割有抵抗力。T20、T20.6和T21-22的存在表明当Ab-D与sclerostin预结合时Loop2仍被有效切割。这些数据表明Ab-D在T20.6表位的Loop1和Loop3侧结合，从而定义了图21中显示的较小的“T20.6衍生物1(胱氨酸结+4臂)”表位。
实施例5
抗Sclerostin单克隆抗体在小鼠中的体内测试
4周大的BDF1雄性小鼠从Charles River Laboratories(Raleigh，NC)获得且饲养在干净笼框中，每笼5只动物。室温维持在68－72oF，且相对湿度维持在34－73％。实验室饲养笼具有12小时的光/暗循环且符合所有AAALAC规范。研究中的所有小鼠的临床观察每天进行一次。
纯化的抗sclerostin单克隆抗体(Ab-A图1；Ab-B图2；Ab-C图3；Ab-D图4)在无菌Dulbecco氏磷酸盐缓冲盐水中进行稀释。小鼠用抗sclerostin抗体或PBS媒介物以21μl/克体重进行皮下注射，以25mg/kg每周2次(星期一和星期四)。人PTH(1-34)在PTH缓冲液(0.001N HCl，0.15M NaCl，2％BSA)中稀释，且以21μl/克体重皮下给药，以100μg/kg每周5次(星期一、星期二、星期三、星期四、星期五)作为阳性对照(图5和6)。每组的小鼠数目在图5和6中是N＝5，且在图7中是N＝6。
PIXImus体内骨密度测定
骨矿物质密度(BMD)在胫骨上段和腰椎通过外周双能X射线骨吸收测量仪(pDEXA)与来自GE/Lunar Medical Systems，Madison，WI的PIXImus2系统每周测定一次。设置25mm2感兴趣区域(ROI)以包括近端关节面、骺和胫骨干骺端上的近端。设置感兴趣区域(ROI)以包括腰椎(L1-L5)。分析胫骨近端和腰区以测定总骨矿物质密度。报告组平均值±标准差并与媒介物治疗组比较用于统计分析。
统计分析
统计分析使用Dunnett’s和Tukey-Kramer进行(对于BMD数据使用MS Excel和JMPv.5.0.)。当P值小于0.05(P<0.05)时，关于每个数据集的组平均值视为显著不同。
抗体的Sclerostin中和活性
与媒介物比较，对于Ab-A(图5)、Ab-B(图5)、Ab-C(图6)和Ab-D(图7)中的每一种可见BMD中的统计上显著增加，证实这4种抗体是sclerostin中和抗体。此外这种数据显示对于结合小鼠sclerostin的抗sclerostin抗体，如上所述的小鼠处理和分析可以用于鉴定sclerostin中和抗体。
实施例6
关于阻断抗体与人sclerostin结合的抗体的筛选测定法
人sclerostin使用标准胺偶联化学与CM5Biacore芯片偶联以产生sclerostin包被表面。300共振单位的sclerostin与表面偶联。
待测试抗体在HBS-EP缓冲液(10mM HEPES pH 7.4，150mM NaCl，3mM EDTA，0.005％(v/v)表面活性剂P20)中稀释至200ug/ml的浓度，并随后以1：1摩尔比(在结合位点的基础上)混合以产生测试混合物。这种测试混合物因此包含浓度为100ug/ml(在结合位点的基础上为1.3um)的每种抗体。同样制备了单独包含测试混合物中一种抗体的各种溶液。这些溶液包含在HBS-EP缓冲液中浓度为100ug/ml(在结合位点的基础上为1.3um)的抗体个体。
20μL测试混合物以10μL/分钟的流速流经sclerostin包被的Biacore芯片且记录结合的量。芯片随后用30mM HCl 2次60秒脉冲处理以便去除所有结合的抗体。只包含测试混合物的抗体之一的溶液(在与测试混合物相同的缓冲液中在结合位点的基础上为1.3μm)随后以与测试混合物相同的方式流经芯片并记录结合的量。芯片再次进行处理以去除所有结合的抗体，且最后包含来自测试混合物的单独另一种抗体的溶液(在与测试混合物相同的缓冲液中在结合位点的基础上为1.3μm)流经芯片并记录结合的量。
下表显示了来自关于一系列不同抗体的交叉阻断测定法的结果。该表每个方格中的值表示当该表顶端行中标明的抗体(在结合位点的基础上为1.3μm)或缓冲液与该表第一列中标明的抗体(在结合位点的基础上为1.3μm)或缓冲液混合时可见的结合量(单位为RU)。
使用上表中关于每种抗体组合的平均结合值(单位为RU)(因为每个组合出现2次)可以计算由每种抗体组合显示的理论结合的百分比。理论结合计算为关于每种测试混合物组分在单独测定时(即抗体和缓冲液)的平均值的总和。
缓冲液 Ab-4 Ab-13 Ab-A Ab-3 Ab-19
缓冲液
Ab-4 90.75 60.45 85.4 60.75
Ab-13 96.9 58.0 97.0
Ab-A 93.5 65.0
Ab-3 94.4
Ab-19
由上述数据显而易见的是Ab-4、Ab-A和Ab-19互相交叉阻断。类似地Ab-13和Ab-3互相交叉阻断。
实施例7
基于ELISA的交叉阻断测定法
在这个实施例中使用的液体体积将是在96孔板ELISA中一般使用的那些(例如50-200μl/孔)。Ab-X和Ab-Y在这个实施例中假定具有约145Kd的分子量且每个抗体分子具有2个sclerostin结合位点。抗sclerostin抗体(Ab-X)在96孔ELISA板[例如Corning 96WellEIA/RIA Flat Bottom Microplate(产品#3590)，Corning Inc.，Acton，MA]上包被(例如50μlμg/ml)至少1小时。这个包被步骤后抗体溶液被去除，板用洗涤溶液(例如PBS和0.05％吐温20)洗涤1次或2次，并随后使用合适的封闭溶液(例如PBS，1％BSA，1％山羊血清和0.5％吐温20)和本领域已知操作进行封闭。封闭溶液随后从ELISA板中去除，且向ELISA板的合适孔中加入在封闭缓冲液中的过量(例如50μl 10μg/ml)次级抗sclerostin抗体(Ab-Y)，所述次级抗sclerostin抗体被测试其交叉阻断包被抗体的能力。这之后，随后向合适孔中加入在封闭缓冲液中的有限量(例如50μl 10ng/ml)sclerostin，且使板于室温在振荡时孵育至少1小时。板随后用洗涤溶液洗涤2－4次。向ELISA板中加入在封闭缓冲液中的合适量的sclerostin检测试剂[例如已与合适量的链霉亲和素-辣根过氧化物酶(HRP)缀合物预复合的生物素化的抗sclerostin多克隆抗体]，并于室温孵育至少1小时。板随后用洗涤溶液洗涤至少4次，且用合适试剂[例如HRP底物例如TMB(比色的)或各种HRP发光底物]显色。
关于该测定法的背景信号定义为在含包被抗体(在这种情况下是Ab-X)、第二种溶液相抗体(在这种情况下是Ab-Y)、只有sclerostin缓冲液(即没有sclerostin)和sclerostin检测试剂的孔中获得的信号。关于该测定法的阳性对照信号定义为在含包被抗体(在这种情况下是Ab-X)、只有第二种溶液相抗体缓冲液(即没有第二种溶液相抗体)、sclerostin和sclerostin检测试剂的孔中获得的信号。ELISA测定法必须以这样的方式进行，以便使阳性对照信号是背景信号的至少6倍。
为了避免由何种抗体用作包被抗体和何种用作第二种(竞争者)抗体的选择产生的任何假象(例如，Ab-X和Ab-Y之间对于sclerostin的显著不同的亲和力)，交叉阻断测定法必须以2种形式进行：
1)形式1是其中Ab-X是包被在EILSA板上的抗体并且Ab-Y是在溶液中的竞争者抗体
和
2)形式2是其中Ab-Y是包被在EILSA板上的抗体并且Ab-X是在溶液中的竞争者抗体。
如果在形式1或形式2中，与在不存在溶液相抗sclerostin抗体的情况下(即阳性对照孔)获得的sclerostin检测信号比较，溶液相抗sclerostin抗体能够引起sclerostin检测信号(即由包被抗体结合的sclerostin量)减少60％－100％、特别是70％－100％、且更特别是80％－100％，那么Ab-X和Ab-Y被定义为交叉阻断的。
在ELISA中使用标记形式的sclerostin的情况下，例如N末端His标记的sclerostin(R&D Systems，Minneapolis，MN，USA；2005目录#1406-ST-025)，那么合适类型的sclerostin检测试剂将包括HRP标记的抗His抗体。除使用N末端His标记的sclerostin之外，还可以使用C末端His标记的sclerostin。此外，本领域已知的各种其他标记和标记结合蛋白组合可以用于这种基于ELISA的交叉阻断测定法中(例如HA标记与抗HA抗体；FLAG标记与抗FLAG抗体；生物素标记与链霉亲和素)。
实施例8
用于鉴定能够拮抗Sclerostin活性的试剂的基于细胞的矿化测定法
引言
将培养的成骨细胞谱系细胞(原代细胞或细胞系)的矿化用作骨形成的体外模型。从经由一种或多种分化试剂诱导的成骨细胞谱系细胞分化开始，矿化需要约1至6周的时间发生。整个系列事件涉及细胞增殖、分化、细胞外基质产生、基质成熟和最终矿物质沉积，所述矿物质沉积指磷酸钙结晶化和/或沉积。以细胞增殖和分化开始、且以矿物质沉积结束的这种系列事件在本文中称为矿化。钙(矿物质)的测量是测定法的输出结果。
矿物质沉积具有强生物物理学特征，因为一旦矿物质“种子”开始形成，将在整个培养中沉积的矿物质总量有时可以非常快速地沉积，例如在其后数天内。培养中的矿物质沉积的时间和程度部分受使用的具体成骨细胞谱系细胞/细胞系、生长条件、分化试剂的选择和细胞培养基中使用的特定血清批号的影响。对于成骨细胞谱系细胞/细胞系矿化培养，应当测试来自超过一个供应商的至少8到15种血清批次以便鉴定允许矿化发生的特定血清批次。
MC3T3-E1细胞(Sudo H等人，In vitro differentiation and calcification ina new clonal osteogenic cell line derived from newborn mouse calvaria.J.CellBiol.96:191-198)和原始细胞系的亚克隆在分化试剂的存在下生长后可以在培养中形成矿物质。此类亚克隆包括MC3T3-E1-BF(Smith E，Redman R，Logg C，Coetzee G，KasaharaN，Frenkel B.2000.Glucocorticoids inhibit developmental stage-specificosteoblast cell cycle.J.Biol.Chem.275:19992-20001)。
Sclerostin中和抗体的鉴定
MC3T3-E1-BF细胞用于矿化测定法。抗坏血酸和B-甘油磷酸用于诱导MC3T3-E1-BF细胞分化导致矿物质沉积。96孔形式的具体筛选方案涉及在星期三接种细胞，随后在12天内更换7次培养基(如下文进一步描述的)，而大部分矿物质沉积在最后大约18小时(例如星期天晚上到星期一)内发生。对于任何给定处理，使用3个孔(N＝3)。矿物质沉积的具体时间和程度可以部分依使用的特定血清批号而变。如细胞培养实验领域一般众所周知的，对照实验将允许消除此类变数。
在这种测定法系统中sclerostin抑制逐渐导致且包括矿物质沉积的系列事件中的一个或多个(即sclerostin抑制矿化)。能够中和sclerostin抑制活性的抗sclerostin抗体允许培养物在sclerostin的存在下矿化，从而使得与只有sclerostin(即无抗体)的处理组中测量的钙量比较，磷酸钙(作为钙测量)沉积中存在统计上显著的增加。对于统计分析(使用MS Excel和JMP)，单向ANOVA随后为Dunnett’s比较用于测定组间差异。当P值小于0.05(P<0.05)时，关于每个数据集的组平均值视为显著不同。来自这种测定法运行的代表性结果显示于图22中。在不存在重组小鼠sclerostin的情况下，逐渐导致且包括矿物质沉积的系列事件正常进行。每个处理组中的钙水平显示为平均值±平均值的标准差(SEM)。在这个示例性实验中，来自钙测定法的钙水平是～31μg/ml。然而，重组小鼠sclerostin的添加导致矿化抑制，且钙减少～85％。与只有sclerostin的组比较，抗sclerostin单克隆抗体Ab-19或Ab-4连同重组sclerostin的添加导致矿物质沉积中统计上显著的增加，因为sclerostin的抑制活性被任一抗体中和。来自这个实验的结果表明Ab-19和Ab-4是sclerostin中和单克隆抗体(Mab)。
图23显示使用重组人sclerostin和2种人源化抗sclerostin Mab的非常类似的结果。图24同样显示了使用如标明的重组人sclerostin以及小鼠和人源化抗sclerostin Mab的非常类似的结果。
显示于图22、23和24中用于实验的抗体具有约145Kd的分子量且每个抗体分子具有2个sclerostin结合位点。
详细的MC3T3-E1-BF细胞培养方案在下文描述。
试剂和培养基
制造的α-MEM通常具有1年的有效期。对于细胞培养使用不超过制造日期后6个月的α-MEM。
扩增培养基(α-MEM/10％FBS/PenStrepGlu)如下制备：
500ml瓶的FBS进行解冻且通过0.22微米过滤器进行无菌过滤。
向1升α-MEM中加入100mls的这种FBS，随后加入10mls100x PenStrepGlutamine。未使用的FBS进行等分且再次冷冻用于以后使用。
分化培养基(α-MEM/10％FBS/PenStrepGlu，+50μg/ml抗坏血酸，+10mMβ-甘油磷酸)如下制备：
100ml分化培养基通过用抗坏血酸和β-甘油磷酸补充100ml扩增培养基如下制备：
分化培养基仅在分化培养基将用于细胞培养的当天通过补充扩增培养基进行制备。分化培养基中抗坏血酸的最终浓度是100μg/ml，因为α-MEM已包含50μg/ml抗坏血酸。抗坏血酸贮存液(10mg/ml)被制备和等分用于冷冻于-80℃。每个等分试样只使用一次(即不再次冷冻)。β-甘油磷酸贮存液(1M)被制备和等分用于冷冻于-20℃。每个等分试样在被丢弃前最多冷冻和解冻5次。
用于扩增MC3T3-E1-BF细胞的细胞培养。
细胞培养在37℃和5％CO2下进行。为了筛选sclerostin中和抗体的目的产生细胞库。细胞库如下制备：
1瓶冷冻MC3T3-E1-BF细胞通过在37℃水浴中搅动来解冻。解冻的细胞置于50ml管中的10ml扩增培养基(α-MEM/10％FBS/PenStrepGlu)内且轻轻旋转5分钟。细胞随后重悬浮于4mlα-MEM/10％FBS/PenStrepGlu中。使用台盼蓝和血球计测定细胞数目后，1x 106细胞在1个T175烧瓶中的50mlα-MEM/10％FBS/PenStrepGlu培养基中铺板。
当这次传代汇合时(大约7天时)，细胞用胰蛋白酶/EDTA(0.05％胰蛋白酶；0.53mMEDTA)进行胰蛋白酶处理，轻轻旋转5分钟且随后重悬浮于5mlα-MEM/10％FBS/PenStrepGlu中。使用台盼蓝和血球计测定细胞数目后，细胞以1x 106细胞在每个T175烧瓶中的50mlα-MEM/10％FBS/PenStrepGlu培养基中铺板。在这个点上用于铺板的T175烧瓶的数目取决于下一传代的可用总细胞数目和所需烧瓶数目。过剩细胞在90％FBS/10％DMSO中以1-2x106活细胞/ml冻结。
当这次传代汇合时(约3－4天)，细胞用胰蛋白酶/EDTA(0.05％胰蛋白酶；0.53mMEDTA)进行胰蛋白酶处理，轻轻旋转5分钟且随后重悬浮于5mlα-MEM/10％FBS/PenStrepGlu中。使用台盼蓝和血球计测定细胞数目后，细胞以1x 106细胞在每个T175烧瓶中的50mlα-MEM/10％FBS/PenStrepGlu培养基中铺板。在这个点上用于铺板的T175烧瓶的数目取决于下一传代的可用总细胞数目和所需烧瓶数目。过剩细胞在90％FBS/10％DMSO中以1-2x106活细胞/ml冻结。
当这次传代汇合时(约3－4天)，细胞用胰蛋白酶/EDTA(0.05％胰蛋白酶；0.53mMEDTA)进行胰蛋白酶处理，轻轻旋转5分钟且随后重悬浮于5mlα-MEM/10％FBS/PenStrepGlu中。使用台盼蓝和血球计测定细胞数目后，细胞以1x 106细胞在每个T175烧瓶中的50mlα-MEM/10％FBS/PenStrepGlu培养基中铺板。在这个点上用于铺板的T175烧瓶的数目取决于下一传代的可用总细胞数目和所需烧瓶数目。过剩细胞在90％FBS/10％DMSO中以1-2x106活细胞/ml冻结。
当这次传代汇合时(约3－4天)，细胞用胰蛋白酶/EDTA(0.05％胰蛋白酶；0.53mMEDTA)进行胰蛋白酶处理，轻轻旋转5分钟且随后重悬浮于5mlα-MEM/10％FBS/PenStrepGlu中。使用台盼蓝和血球计测定细胞数目后，细胞在90％FBS/10％DMSO中以1-2x106活细胞/ml冻结。这个“最后传代”的冷冻细胞是用于筛选测定法的细胞代。
用于MC3T3-E1-BF细胞矿化的细胞培养。
细胞培养在37℃和5％CO2下进行。在细胞培养矿化操作时希望最小化温度和％CO2波动。这可以通过最小化板在加液时在孵育箱外消耗的时间以及通过最小化细胞培养矿化操作时孵育箱门打开和关闭的次数来达到。在这点上具有专门用于细胞培养矿化的组织培养箱(且因此不会不必要的打开和关闭)可以是有帮助的。
如上所述制备的合适数目的“最后传代”瓶通过在37℃水浴中搅动来解冻。解冻的细胞置于50ml管中的10ml扩增培养基(α-MEM/10％FBS/PenStrepGlu)内且轻轻旋转5分钟。细胞随后重悬浮于4mlα-MEM/10％FBS/PenStrepGlu中。通过台盼蓝和血球计测定细胞数目后，2500个细胞在胶原I包被的96孔板(Becton Dickinson Labware，目录#354407)的每孔200微升扩增培养基中铺板。
为了避免矿化板边缘效应，细胞自始至终不在板周围最外面的行/列中铺板。改为向这些最外面的行/列的孔中加入200微升PBS。
示例性细胞培养操作
在下列操作中，用于细胞铺板的起始日指定为星期三。如果一周的另一天用作用于细胞铺板的起始日，那么这一天将触发如下文指出的整个过程中去除和添加培养基的日时间表。例如，如果细胞在星期二铺板，那么培养基不应在第一个星期五和星期六去除和添加，也不应在第二个星期五和星期六去除和添加。由星期二开始时，板将制备用于在最后星期日的钙测定。
细胞在星期三以2500个细胞在200μl扩增培养基中铺板。
在星期四所有扩增培养基被去除且加入200μl分化培养基。
在星期五100μl培养基被去除且加入100μl新鲜的分化培养基。
在星期一100μl培养基被去除且加入100μl新鲜的分化培养基。
在星期二100μl培养基被去除且加入100μl新鲜的分化培养基。
在星期三100μl培养基被去除且加入100μl新鲜的分化培养基。
在星期四100μl培养基被去除且加入100μl新鲜的分化培养基。
在星期五100μl培养基被去除且加入100μl新鲜的分化培养基。
在接下来的星期一板如下制备用于钙测定：
板用10mM Tris，HCl pH 7-8洗涤1次。
在通风橱中操作，每孔加入200μl 0.5N HCl。板随后冷冻于-80℃。
就在测量钙之前，板被冷冻-解冻2次，且随后用多通道吸液管吹打用于分散板内含物。随后允许板内含物于4℃沉积30分钟，在这个点上取出合适量的上清液用于使用商购可得的钙试剂盒测量钙。示例性和非限制性试剂盒是Calcium(CPC)Liquicolor，目录号0150-250，Stanbio Laboratory，Boerne，TX。
在这种基于细胞的测定法中，sclerostin抑制逐渐导致且包括矿物质沉积的系列事件中的一个或多个(即sclerostin抑制矿化)。因此，在其中特定细胞培养实验包括sclerostin的实验中，从第一个星期四开始以及其后的每个加液日向培养基中加入重组sclerostin。在其中抗sclerostin单克隆抗体(Mab)被测试中和sclerostin能力的情况下，即通过中和sclerostin抑制矿化的能力允许矿化，从第一个星期四开始以及其后的每个加液日向培养基中加入Mab。根据该方案，这如下完成：Mab在分化培养基中与重组sclerostin一起于37℃预孵育45－60分钟，且随后这种培养基用于给细胞加液。
上述是用于MC3T3-E1-BF细胞的12天矿化方案。使用相同试剂和加液方案，我们从RIKEN细胞库(RCB 1126，RIKEN BioResource Center 3-1-1Koyadai,Tsukuba-shi，Ibaraki 305-0074Japan)获得的原始MC3T3-E1细胞(Sudo H，Kodama H-A，Amagai Y，Yamamoto S，Kasai S.1983.In vitro differentiation and calcification in a newclonal osteogenic cell line derived from newborn mouse calvaria.J Cell Biol96:191-198)需要比MC3T3-E1-BF细胞更长的时间矿化(矿化需要总共20天)。原始MC3T3-E1细胞的矿化被重组sclerostin抑制，且这种抑制使用sclerostin中和抗体被阻断。
实施例9
抗Sclerostin抗体在SCID小鼠的CD4CD45RBHI结肠炎转移模型中保护不受炎症诱导的骨丢失
模型概述
将CD4+T细胞的CD45RB高亚群注射到C.B-17scid小鼠中导致慢性肠炎症，其特征类似于人炎性肠病(IBD)的那些。腹泻和衰弱性疾病在细胞转移后3－5周出现，结肠内有严重的白细胞浸润伴随上皮细胞增生和肉芽肿形成。接受CD4+细胞的相反亚群－表达CD45RB低的那些－的C.B-17scid小鼠没有显示结肠炎，且具有与未注射的scid小鼠不能区别的体重增加。除结肠炎症状之外，CD4+CD45RB高T细胞结肠炎转移模型伴随骨矿物质密度(BMD)减少，被认为主要是通过炎症机制而不是饮食吸收不良造成的(Byrne，F.R.等人，Gut54:78-86，2005)。
结肠炎的诱导和炎症诱导的骨丢失
从雌性balb/c小鼠获取脾且通过70μm细胞过滤网破裂。CD4+群体随后通过使用针对B220、MAC-1、CD8和I-AD的抗体用Dynabeads负选择来富集。富集的群体随后用FITC缀合的抗CD4和PE缀合的抗CD45RB染色且通过在Moflo(Dakocytomation)上双色分选分成CD4+CD45RB高和CD4+CD45RB低群体。CD45RB高和CD45RB低群体分别定义为CD4+细胞最亮染色的40％和最暗染色的20％。随后在第0天将5X 105细胞腹膜内注射到C.B-17scid小鼠内，且通过软便或腹泻和体重减轻的出现监控结肠炎的发生。骨矿物质密度测量在研究结束时(第88天)进行。
抗Sclerostin治疗对结肠炎症状和BMD的影响
Ab-A IgG从CD4+CD45RB高细胞转移前一天起以10mg/kg皮下给药，且与接受阴性对照抗体101.4(同样以10mg/kg皮下给药)的小鼠比较。其后抗体每周给药一次。接受非病原性CD4+CD45RB低细胞且以10mg/kg 101.4给药的小鼠组作为对照进行研究。在研究结束时(第88天)进行骨矿物质密度测量且获取结肠切片用于分析细胞浸润和评估组织学损害。
a)对结肠炎症状没有影响
一般的结肠炎症状例如体重减轻和炎症细胞浸润到结肠内不受Ab-A治疗的影响。类似地用Ab-A治疗后对结肠的组织学损害没有改善。
b)抑制炎症诱导的骨矿物质密度损失。
在细胞转移到C.B-17scid小鼠内后第88天时，测量骨矿物质密度(总BMD、椎骨BMD和股骨BMD)。如图25中所示，与接受CD4+CD45RB低非病原性细胞的对照小鼠相比，接受CD4+CD45RB高T细胞和阴性对照抗体101.4的小鼠具有减少的骨矿物质密度。相反，用Ab-A治疗后没有注意到BMD中的减少。总之，BMD的椎骨和股骨测量结果在接受CD4+CD45RB高T细胞和用Ab-A治疗的小鼠中明显高于接受CD4+CD45RB高T细胞和用101.4治疗的小鼠(通过Bonferroni多重比较检验的P<0.001)。
实施例10
针对人sclerostin的抗sclerostin抗体的基于KinExA的亲和力测定(KD)
针对人sclerostin的几种抗sclerostin抗体的亲和力通过溶液平衡结合分析使用3000(Sapidyne Instruments Inc.，Boise，ID)进行评估。对于这些测量，Reacti-Gel 6x珠(Pierce，Rockford，IL)在50mM Na2CO3，pH 9.6中用40μg/ml人sclerostin于4℃进行预包被过夜。珠随后在1M Tris-HCl，pH 7.5中用1mg/ml BSA于4℃封闭2小时。10pM、30pM或100pM抗体与浓度为0.1pM－1nM的各种浓度人sclerostin混合，且在PBS中用0.1mg/ml BSA和0.005％P20于室温平衡超过8小时。混合物随后流经人sclerostin包被的珠。珠结合的抗sclerostin抗体的量使用分别对于小鼠或人抗体样品的荧光Cy5标记的山羊抗小鼠IgG或荧光Cy5标记的山羊抗人IgG抗体(Jackson Immuno Research，WestGrove，PA)进行定量。测量的荧光信号的量与处于平衡的每种反应混合物中的游离抗sclerostin抗体浓度成比例。解离平衡常数(KD)使用KinExA Pro软件中提供的n曲线单位点同种结合模型由竞争曲线的非线性回归获得。关于所选抗体的KinExA测定法结果概括于下表中。
实施例11
用于测定人源化抗sclerostin抗体对于人sclerostin的亲和力的Biacore方法
BIAcore技术实时且无需标记地监控生物分子之间的结合。称为配体的相互作用物之一直接固定或捕获在固定表面上，而称为分析物的另一种相互作用物在溶液中流经捕获表面。当分析物与配体结合以在表面上形成复合物时，传感器检测传感器表面上的物质的变化。这对应结合过程。当分析物用缓冲液替换时监控解离过程。在亲和力BIAcore测定法中，配体是抗sclerostin抗体并且分析物是sclerostin。
仪器
3000，Biacore AB，Uppsala，Sweden
传感器芯片
CM5(研究级)目录号：BR-1001-14，Biacore AB，Uppsala，Sweden。芯片贮存于4℃。
BIAnormalising溶液
70％(w/w)丙三醇。Part of BIAmaintenance Kit目录号：BR-1002-51，BiacoreAB，Uppsala，Sweden。BIAmaintenance试剂盒贮存于4℃。
胺偶联试剂盒
目录号：BR-1000-50，Biacore AB，Uppsala，Sweden.
乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐(EDC)。在蒸馏水中制备成75mg/mL且以200μL的等分试样贮存于-70℃。
N-羟基琥珀酰亚胺(NHS)。在蒸馏水中制备成11.5mg/mL且以200μL的等分试样贮存于-70℃。
1M乙醇胺盐酸盐-NaOH pH 8.5。以200μL的等分试样贮存于-70℃。
缓冲液
用于固定捕获抗体的运行缓冲液：HBS-EP(0.01M HEPES pH7.4，0.15M NaCl，3mMEDTA，0.005％表面活性剂P20).目录号：BR-1001-88，Biacore AB，Uppsala，Sweden。缓冲液贮存于4℃。
固定缓冲液：乙酸盐5.0(10mM乙酸钠pH 5.0).目录号：BR-1003-51，Biacore AB，Uppsala，Sweden。缓冲液贮存于4℃。
关于结合测定法的运行缓冲液：含1mg/mL的CM-葡聚糖(目录号27560，FlukaBioChemika，Buchs，Switzerland)的HBS-EP(0.01M HEPES pH 7.4，0.15M NaCl，3mM EDTA，0.005％表面活性剂P20，目录号：BR-1001-88，Biacore AB，Uppsala，Sweden)。缓冲液贮存于4℃。
配体捕获
Affinipure F(ab’)2片段山羊抗人IgG，Fc片段特异性。Jackson ImmunoResearchInc(Pennsylvania，USA)目录号：109-006-098。试剂贮存于4℃。
配体
人源化抗人sclerostin抗体Ab5、Ab14和Ab20。
分析物
重组人sclerostin。等分试样贮存于-70℃且对于每次测定法解冻1次。
再生溶液
40mM HCl通过用蒸馏水稀释由11.6M贮存液(BDH，Poole，England.目录号：101254H)制备。
5mM NaOH通过用蒸馏水稀释由50mM贮存液制备。目录号：BR-1003-58，BiacoreAB，Uppsala，Sweden。
测定方法
测定形式是通过固定的抗人IgG-Fc捕获抗sclerostin抗体随后在捕获表面上滴定sclerostin。
操作的例子在下文给出：
BIA(Biamolecular Interaction Analysis)使用BIAcore 3000(BIAcore AB)进行。Affinipure F(ab’)2片段山羊抗人IgG(Fc片段特异性)(Jackson ImmunoResearch)经由胺偶联化学在CM5传感器芯片上固定至≈4000共振单位(RU)的捕获水平。包含1mg/mLCM-葡聚糖的HBS-EP缓冲液(10mM HEPES pH 7.4，0.15M NaCl，3mM EDTA，0.005％表面活性剂P20，BIAcore AB)用作运行缓冲液，而流速为10μl/分钟。以～5μg/mL注射的10μl抗sclerostin抗体用于被固定的抗人IgG-Fc捕获。抗体捕获水平一般为100-200RU。各种浓度的Sclerostin以30μL/分钟的流速在捕获的抗sclerostin抗体上滴定。表面通过以10μL/分钟的流速注射2次10μL的40mM HCl，随后为注射5μL的5mM NaOH得到再生。
扣除背景的结合曲线使用BIAevaluation软件(版本3.2)根据标准程序进行分析。动力学参数由拟合算法来测定。
动力学数据和计算的解离常数在表2中给出。
表2：抗sclerostin抗体对于sclerostin的亲和力
抗体 ka(1/Ms) kd(1/s) Kd(pM)
Ab-5 1.78E+06 1.74E-04 97.8
Ab-14 3.30E+06 4.87E-06 1.48
Ab-20 2.62E+06 4.16E-05 15.8
实施例12
抗Sclerostin单克隆抗体在短尾猴(cynomolgus monkey)中的体内测试
33只大约3-5岁大的雌性短尾猴(食蟹猴(Macaca fascicularis))在这项2个月的研究中使用。该研究包含11个组：
组1：媒介物(N＝4)
组2：Ab-23(N＝2，剂量3mg/kg)
组3：Ab-23(N＝3，剂量10mg/kg)
组4：Ab-23(N＝3，剂量30mg/kg)
组5：Ab-5(N＝3，剂量3mg/kg)
组6：Ab-5(N＝3，剂量10mg/kg)
组7：Ab-5(N＝3，剂量30mg/kg)
组8：Ab-14(N＝3，剂量3mg/kg)
组9：Ab-14(N＝3，剂量10mg/kg)
组10：Ab-14(N＝3，剂量30mg/kg)
组11：甲状旁腺激素(1-34)[PTH(1-34)](N＝3，剂量10ug/kg)
所有给药都是皮下的。PTH(1-34)每天给药，单克隆抗体(Mab)给药2次(第一次剂量在研究开始时且第二次剂量在一个月的时间点时)。为了评估骨参数(例如骨矿物质密度)，pQCT(外周定量计算机断层摄影术)和DXA(双能X射线骨吸收测量仪)扫描在研究开始前(以获得基线值)和在一个月后(在第二次Mab给药前)以及最后在研究结束时(2个月的时间点)进行，在该点上猴进行尸检用于进一步分析(例如组织形态测定分析)。动物进行荧光染料标记(第14、24、47和57天)用于动态组织形态测定。在研究时的各个时间点上收集血清[第1天给药前(第一次Mab给药当天)、第1天给药后12小时、第2天、第3天、第5天、第7天、第14天、第21天、第28天、第29天给药后12小时(第29天是第二次和最后一次Mab给药当天)、第30天、第31天、第33天、第35天、第42天、第49天和第56天]。
3种骨相关血清生物标记使用商购可得试剂盒进行测量：
骨钙蛋白(OC)(DSL Osteocalcin Radioimmunoassay Kit；Diagnostic SystemsLaboratories，Inc.,Webster，TX，USA)
I型前胶原N末端前肽(P1NP)(P1NP Radioimmunoassay Kit；Orion Diagnostica，Espoo，Finland)
I型胶原al链的C端肽片段(sCTXI)(SerumELISA；NordicBioscience Diagnostics A/S，Herlev，Denmark).
pQCT和DXA扫描在众多骨骼位点(包括胫骨干骺端和骨干、桡骨干骺端和骨干、股骨颈、腰椎)产生关于各种骨参数(包括骨矿物质密度(BMD)和骨矿物质含量)的数据。与媒介物组比较，在对于每种Mab的某些时间点和剂量上的某些参数中，这种骨数据(对于每个动物相对于基线的百分比变化)和合成代谢(OC，P1NP)血清生物标记数据(对于每个动物相对于基线的百分比变化)分析显示统计上显著的增加。这种骨参数数据、血清生物标记数据、以及组织形态测定数据指出3种Mab(Ab-23、Ab-5和Ab-14)中的每一种在短尾猴中都能够中和sclerostin。这种活性对于Ab-23和Ab-5最强，特别是在最高剂量(30mg/kg)时，伴随骨形成(合成作用)以及骨净增加(例如BMD)中的显著增加。骨参数和合成代谢组织形态测定参数中统计上显著的增加同样在阳性对照组(PTH(1-34))中发现。
血清骨形成标记(P1NP，骨钙蛋白)在各个时间点和剂量上是增加的(与媒介物(VEH)比较p<0.05)，但特别是对于Ab-23和Ab-5在30mg/kg组中。组织形态测定分析显示在Ab-23和Ab-5的较高剂量时腰椎和胫骨近端的松质骨成骨速度(高达5倍的增加)以及在股骨中段内皮质表面(endocortical surface)(高达10倍的增加)中的显著增加(与VEH比较p<0.05)。对于高剂量的Ab-23和Ab-5在腰椎中小梁厚度增加(>60％，与VEH比较p<0.05)。在研究结束时(2个月)，作为相对于基线的百分比变化的面积BMD在股骨颈、桡骨超远端(Ab-23，30mg/kg)和腰椎(Ab-5，30mg/kg)处增加(与VEH比较p<0.05)。在腰椎处面积BMD中的增加伴随椎骨强度中的增加(对于Ab-23，30mg/kg，椎骨最大载量增加97％；与VEH比较p<0.05)；在Mab给药前关于腰部面积BMD的基线值在所有组中是统计上相似的。总之，在短尾猴中sclerostin中和Mab的短期施用部分导致骨形成、BMD和椎骨强度的增加。
尽管为了举例说明的目的已在本文中描述了本发明的具体实施方案，但前述内容无需背离本发明的精神和范围即可进行各种修饰。因此，本发明除了如附加权利要求外不受限制。本文公开的所有出版物、公开的专利申请和专利文件在此引入作为参考。
序列表
<110> UCB S.A.
Amgen, Inc.
<120> Sclerostin结合剂
130> 60117-225
<150>
<151> 2006-04-25
<150>
<151> 2006-04-17
<150> 60/782,244
<151> 2006-03-13
<150> 60/776,847
<151> 2006-02-24
<150> 60/667,583
<151> 2005-05-03
<160> 396
<170> FastSEQ for Windows Version 4.0
<210> 1
<211> 190
<212> PRT
<213> 智人
<400> 1
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Glu
1 5 10 15
Leu Gly Glu Tyr Pro Glu Pro Pro Pro Glu Leu Glu Asn Asn Lys Thr
20 25 30
Met Asn Arg Ala Glu Asn Gly Gly Arg Pro Pro His His Pro Phe Glu
35 40 45
Thr Lys Asp Val Ser Glu Tyr Ser Cys Arg Glu Leu His Phe Thr Arg
50 55 60
Tyr Val Thr Asp Gly Pro Cys Arg Ser Ala Lys Pro Val Thr Glu Leu
65 70 75 80
Val Cys Ser Gly Gln Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile
85 90 95
Gly Arg Gly Lys Trp Trp Arg Pro Ser Gly Pro Asp Phe Arg Cys Ile
100 105 110
Pro Asp Arg Tyr Arg Ala Gln Arg Val Gln Leu Leu Cys Pro Gly Gly
115 120 125
Glu Ala Pro Arg Ala Arg Lys Val Arg Leu Val Ala Ser Cys Lys Cys
130 135 140
Lys Arg Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly
145 150 155 160
Thr Glu Ala Ala Arg Pro Gln Lys Gly Arg Lys Pro Arg Pro Arg Ala
165 170 175
Arg Ser Ala Lys Ala Asn Gln Ala Glu Leu Glu Asn Ala Tyr
180 185 190
<210> 2
<211> 14
<212> PRT
<213> 智人
<400> 2
Asp Val Ser Glu Tyr Ser Cys Arg Glu Leu His Phe Thr Arg
1 5 10
<210> 3
<211> 18
<212> PRT
<213> 智人
<400> 3
Ser Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro
1 5 10 15
Ala Arg
<210> 4
<211> 16
<212> PRT
<213> 智人
<400> 4
Trp Trp Arg Pro Ser Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr
1 5 10 15
<210> 5
<211> 12
<212> PRT
<213> 智人
<400> 5
Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg
1 5 10
<210> 6
<211> 26
<212> PRT
<213> 智人
<400> 6
Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp
1 5 10 15
Trp Arg Pro Ser Gly Pro Asp Phe Arg Cys
20 25
<210> 7
<211> 214
<212> PRT
<213> Mus musculus
<400> 7
Asp Val Gln Met Ile Gln Ser Pro Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Ile Val Thr Met Thr Cys Gln Ala Ser Gln Gly Thr Ser Ile Asn
20 25 30
Leu Asn Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ser Ser Asn Leu Glu Asp Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Asp
65 70 75 80
Glu Asp Leu Ala Thr Tyr Phe Cys Leu Gln His Ser Tyr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 8
<211> 645
<212> DNA
<213> Mus musculus
<400> 8
gatgtccaga tgattcagtc tccatcctcc ctgtctgcat ctttgggaga catagtcacc 60
atgacttgcc aggcaagtca gggcactagc attaatttaa actggtttca gcaaaaacca 120
gggaaggctc ctaagctcct gatctatggt tcaagcaact tggaagatgg ggtcccatca 180
aggttcagtg gcagtagata tgggacagat ttcactctca ccatcagcag cctggaggat 240
gaagatctgg caacttattt ctgtctacaa catagttatc tcccgtacac gttcggaggg 300
gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645
<210> 9
<211> 236
<212> PRT
<213> Mus musculus
<400> 9
Met Asn Thr Arg Ala Pro Ala Glu Phe Leu Gly Phe Leu Leu Leu Trp
1 5 10 15
Phe Leu Gly Ala Arg Cys Asp Val Gln Met Ile Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Leu Gly Asp Ile Val Thr Met Thr Cys Gln Ala Ser
35 40 45
Gln Gly Thr Ser Ile Asn Leu Asn Trp Phe Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Gly Ser Ser Asn Leu Glu Asp Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Arg Tyr Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Glu Asp Glu Asp Leu Ala Thr Tyr Phe Cys Leu Gln
100 105 110
His Ser Tyr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser
130 135 140
Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn
145 150 155 160
Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu
165 170 175
Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr
195 200 205
Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr
210 215 220
Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 10
<211> 711
<212> DNA
<213> Mus musculus
<400> 10
atgaacacga gggcccctgc tgagttcctt gggttcctgt tgctctggtt tttaggtgcc 60
agatgtgatg tccagatgat tcagtctcca tcctccctgt ctgcatcttt gggagacata 120
gtcaccatga cttgccaggc aagtcagggc actagcatta atttaaactg gtttcagcaa 180
aaaccaggga aggctcctaa gctcctgatc tatggttcaa gcaacttgga agatggggtc 240
ccatcaaggt tcagtggcag tagatatggg acagatttca ctctcaccat cagcagcctg 300
gaggatgaag atctggcaac ttatttctgt ctacaacata gttatctccc gtacacgttc 360
ggagggggga ccaagctgga aataaaacgg gctgatgctg caccaactgt atccatcttc 420
ccaccatcca gtgagcagtt aacatctgga ggtgcctcag tcgtgtgctt cttgaacaac 480
ttctacccca aagacatcaa tgtcaagtgg aagattgatg gcagtgaacg acaaaatggc 540
gtcctgaaca gttggactga tcaggacagc aaagacagca cctacagcat gagcagcacc 600
ctcacgttga ccaaggacga gtatgaacga cataacagct atacctgtga ggccactcac 660
aagacatcaa cttcacccat tgtcaagagc ttcaacagga atgagtgtta g 711
<210> 11
<211> 443
<212> PRT
<213> Mus musculus
<400> 11
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Thr Pro Gly Ala
1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His
20 25 30
Tyr Met Ser Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asn Pro Tyr Ser Gly Glu Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Thr Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Ile Ala Tyr
65 70 75 80
Met Glu Ile Arg Gly Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Asp Tyr Asp Ala Ser Pro Phe Ala Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser Val Tyr
115 120 125
Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu
130 135 140
Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp
145 150 155 160
Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu
165 170 175
Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser
180 185 190
Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser
195 200 205
Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys
210 215 220
Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro
225 230 235 240
Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr
245 250 255
Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser
260 265 270
Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg
275 280 285
Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile
290 295 300
Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn
305 310 315 320
Ser Pro Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys
325 330 335
Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu
340 345 350
Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe
355 360 365
Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala
370 375 380
Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr
385 390 395 400
Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly
405 410 415
Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His
420 425 430
Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440
<210> 12
<211> 1332
<212> DNA
<213> Mus musculus
<400> 12
gaggtccagc tgcaacagtc tggacctgaa ctggtgacgc ctggggcttc agtgaagata 60
tcttgtaagg cttctggata cacattcact gaccactaca tgagctgggt gaagcagagt 120
catggaaaaa gccttgagtg gattggagat attaatccct attctggtga aactacctac 180
aaccagaagt tcaagggcac ggccacattg actgtagaca agtcttccag tatagcctac 240
atggagatcc gcggcctgac atctgaggac tctgcagtct attactgtgc aagagatgat 300
tacgacgcct ctccgtttgc ttactggggc caagggactc tggtcactgt ctctgcagcc 360
aaaacgacac ccccatctgt ctatccactg gcccctggat ctgctgccca aactaactcc 420
atggtgaccc tgggatgcct ggtcaagggc tatttccctg agccagtgac agtgacctgg 480
aactctggat ccctgtccag cggtgtgcac accttcccag ctgtcctgca gtctgacctc 540
tacactctga gcagctcagt gactgtcccc tccagcacct ggcccagcga gaccgtcacc 600
tgcaacgttg cccacccggc cagcagcacc aaggtggaca agaaaattgt gcccagggat 660
tgtggttgta agccttgcat atgtacagtc ccagaagtat catctgtctt catcttcccc 720
ccaaagccca aggatgtgct caccattact ctgactccta aggtcacgtg tgttgtggta 780
gacatcagca aggatgatcc cgaggtccag ttcagctggt ttgtagatga tgtggaggtg 840
cacacagctc agacgcaacc ccgggaggag cagttcaaca gcactttccg ctcagtcagt 900
gaacttccca tcatgcacca ggactggctc aatggcaagg agttcaaatg cagggtcaac 960
agtccagctt tccctgcccc catcgagaaa accatctcca aaaccaaagg cagaccgaag 1020
gctccacagg tgtacaccat tccacctccc aaggagcaga tggccaagga taaagtcagt 1080
ctgacctgca tgataacaga cttcttccct gaagacatta ctgtggagtg gcagtggaat 1140
gggcagccag cggagaacta caagaacact cagcccatca tggacacaga tggctcttac 1200
ttcatctaca gcaagctcaa tgtgcagaag agcaactggg aggcaggaaa tactttcacc 1260
tgctctgtgt tacatgaggg cctgcacaac caccatactg agaagagcct ctcccactct 1320
cctggtaaat ga 1332
<210> 13
<211> 462
<212> PRT
<213> Mus musculus
<400> 13
Met Arg Cys Arg Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Thr
20 25 30
Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp His Tyr Met Ser Trp Val Lys Gln Ser His Gly Lys Ser Leu
50 55 60
Glu Trp Ile Gly Asp Ile Asn Pro Tyr Ser Gly Glu Thr Thr Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Thr Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Ile Ala Tyr Met Glu Ile Arg Gly Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Asp Asp Tyr Asp Ala Ser Pro Phe Ala Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro
130 135 140
Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met
145 150 155 160
Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr
165 170 175
Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro
180 185 190
Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val
195 200 205
Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His
210 215 220
Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys
225 230 235 240
Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe
245 250 255
Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro
260 265 270
Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val
275 280 285
Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr
290 295 300
Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu
305 310 315 320
Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys
325 330 335
Arg Val Asn Ser Pro Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser
340 345 350
Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro
355 360 365
Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile
370 375 380
Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly
385 390 395 400
Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp
405 410 415
Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp
420 425 430
Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His
435 440 445
Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 14
<211> 1389
<212> DNA
<213> Mus musculus
<400> 14
atgagatgca ggtggatctt tctctttctc ctgtcaggaa ctgcaggtgt cctctctgag 60
gtccagctgc aacagtctgg acctgaactg gtgacgcctg gggcttcagt gaagatatct 120
tgtaaggctt ctggatacac attcactgac cactacatga gctgggtgaa gcagagtcat 180
ggaaaaagcc ttgagtggat tggagatatt aatccctatt ctggtgaaac tacctacaac 240
cagaagttca agggcacggc cacattgact gtagacaagt cttccagtat agcctacatg 300
gagatccgcg gcctgacatc tgaggactct gcagtctatt actgtgcaag agatgattac 360
gacgcctctc cgtttgctta ctggggccaa gggactctgg tcactgtctc tgcagccaaa 420
acgacacccc catctgtcta tccactggcc cctggatctg ctgcccaaac taactccatg 480
gtgaccctgg gatgcctggt caagggctat ttccctgagc cagtgacagt gacctggaac 540
tctggatccc tgtccagcgg tgtgcacacc ttcccagctg tcctgcagtc tgacctctac 600
actctgagca gctcagtgac tgtcccctcc agcacctggc ccagcgagac cgtcacctgc 660
aacgttgccc acccggccag cagcaccaag gtggacaaga aaattgtgcc cagggattgt 720
ggttgtaagc cttgcatatg tacagtccca gaagtatcat ctgtcttcat cttcccccca 780
aagcccaagg atgtgctcac cattactctg actcctaagg tcacgtgtgt tgtggtagac 840
atcagcaagg atgatcccga ggtccagttc agctggtttg tagatgatgt ggaggtgcac 900
acagctcaga cgcaaccccg ggaggagcag ttcaacagca ctttccgctc agtcagtgaa 960
cttcccatca tgcaccagga ctggctcaat ggcaaggagt tcaaatgcag ggtcaacagt 1020
ccagctttcc ctgcccccat cgagaaaacc atctccaaaa ccaaaggcag accgaaggct 1080
ccacaggtgt acaccattcc acctcccaag gagcagatgg ccaaggataa agtcagtctg 1140
acctgcatga taacagactt cttccctgaa gacattactg tggagtggca gtggaatggg 1200
cagccagcgg agaactacaa gaacactcag cccatcatgg acacagatgg ctcttacttc 1260
atctacagca agctcaatgt gcagaagagc aactgggagg caggaaatac tttcacctgc 1320
tctgtgttac atgagggcct gcacaaccac catactgaga agagcctctc ccactctcct 1380
ggtaaatga 1389
<210> 15
<211> 218
<212> PRT
<213> Mus musculus
<400> 15
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Thr Val Ser Leu Gly
1 5 10 15
Leu Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala
50 55 60
Arg Phe Ser Gly Asn Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Ala Val Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
115 120 125
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
130 135 140
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
145 150 155 160
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
180 185 190
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
195 200 205
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 16
<211> 657
<212> DNA
<213> Mus musculus
<400> 16
gacattgtgc tgacccaatc tccagcttct ttgactgtgt ctctaggcct gagggccacc 60
atctcctgca aggccagcca aagtgttgat tatgatggtg atagttatat gaactggtac 120
cagcagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa tctagaatct 180
gggatcccag ccaggtttag tggcaatggg tctgggacag acttcaccct caacatccat 240
cctgtggagg aggaggatgc tgtaacctat tactgtcaac aaagtaatga ggatccgtgg 300
acgttcggtg gaggcaccaa gctggaaatc aaacgggctg atgctgcacc aactgtatcc 360
atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 420
aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 480
aatggcgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 540
agcaccctca cgttgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 600
actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgttag 657
<210> 17
<211> 238
<212> PRT
<213> Mus musculus
<400> 17
Met Glu Thr Asp Thr Ile Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Thr
20 25 30
Val Ser Leu Gly Leu Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser
35 40 45
Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser
65 70 75 80
Gly Ile Pro Ala Arg Phe Ser Gly Asn Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Val Thr Tyr Tyr Cys
100 105 110
Gln Gln Ser Asn Glu Asp Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 18
<211> 717
<212> DNA
<213> Mus musculus
<400> 18
atggagacag acacaatcct gctatgggtg ctgctgctct gggttccagg ctccactggt 60
gacattgtgc tgacccaatc tccagcttct ttgactgtgt ctctaggcct gagggccacc 120
atctcctgca aggccagcca aagtgttgat tatgatggtg atagttatat gaactggtac 180
cagcagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa tctagaatct 240
gggatcccag ccaggtttag tggcaatggg tctgggacag acttcaccct caacatccat 300
cctgtggagg aggaggatgc tgtaacctat tactgtcaac aaagtaatga ggatccgtgg 360
acgttcggtg gaggcaccaa gctggaaatc aaacgggctg atgctgcacc aactgtatcc 420
atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 480
aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 540
aatggcgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 600
agcaccctca cgttgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 660
actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgttag 717
<210> 19
<211> 449
<212> PRT
<213> Mus musculus
<400> 19
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Cys
20 25 30
Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asn Pro Phe Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser His Tyr Tyr Phe Asp Gly Arg Val Pro Trp Asp Ala Met
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr
115 120 125
Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr
130 135 140
Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser
180 185 190
Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn
195 200 205
Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro
210 215 220
Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser
225 230 235 240
Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr
245 250 255
Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp
260 265 270
Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr
275 280 285
Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser
290 295 300
Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr
340 345 350
Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr
355 360 365
Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln
370 375 380
Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met
385 390 395 400
Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys
405 410 415
Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu
420 425 430
Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly
435 440 445
Lys
<210> 20
<211> 1350
<212> DNA
<213> Mus musculus
<400> 20
gaggtccagc tgcaacaatc tggacctgag ctggtgaagc ctgggacttc agtgaagatg 60
tcctgtaagg cttctggata cacattcact gactgctaca tgaactgggt gaagcagagc 120
catgggaaga gccttgaatg gattggagat attaatcctt tcaacggtgg tactacctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca aatcctccag cacagcctac 240
atgcagctca acagcctgac atctgacgac tctgcagtct attactgtgc aagatcccat 300
tattacttcg atggtagagt cccttgggat gctatggact actggggtca aggaacctca 360
gtcaccgtct cctcagccaa aacgacaccc ccatctgtct atccactggc ccctggatct 420
gctgcccaaa ctaactccat ggtgaccctg ggatgcctgg tcaagggcta tttccctgag 480
ccagtgacag tgacctggaa ctctggatcc ctgtccagcg gtgtgcacac cttcccagct 540
gtcctgcagt ctgacctcta cactctgagc agctcagtga ctgtcccctc cagcacctgg 600
cccagcgaga ccgtcacctg caacgttgcc cacccggcca gcagcaccaa ggtggacaag 660
aaaattgtgc ccagggattg tggttgtaag ccttgcatat gtacagtccc agaagtatca 720
tctgtcttca tcttcccccc aaagcccaag gatgtgctca ccattactct gactcctaag 780
gtcacgtgtg ttgtggtaga catcagcaag gatgatcccg aggtccagtt cagctggttt 840
gtagatgatg tggaggtgca cacagctcag acgcaacccc gggaggagca gttcaacagc 900
actttccgct cagtcagtga acttcccatc atgcaccagg actggctcaa tggcaaggag 960
ttcaaatgca gggtcaacag tgcagctttc cctgccccca tcgagaaaac catctccaaa 1020
accaaaggca gaccgaaggc tccacaggtg tacaccattc cacctcccaa ggagcagatg 1080
gccaaggata aagtcagtct gacctgcatg ataacagact tcttccctga agacattact 1140
gtggagtggc agtggaatgg gcagccagcg gagaactaca agaacactca gcccatcatg 1200
gacacagatg gctcttactt catctacagc aagctcaatg tgcagaagag caactgggag 1260
gcaggaaata ctttcacctg ctctgtgtta catgagggcc tgcacaacca ccatactgag 1320
aagagcctct cccactctcc tggtaaatga 1350
<210> 21
<211> 468
<212> PRT
<213> Mus musculus
<400> 21
Met Gly Trp Asn Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Tyr Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Thr Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Cys Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu
50 55 60
Glu Trp Ile Gly Asp Ile Asn Pro Phe Asn Gly Gly Thr Thr Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Gln Leu Asn Ser Leu Thr Ser Asp Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser His Tyr Tyr Phe Asp Gly Arg Val Pro Trp
115 120 125
Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
130 135 140
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
145 150 155 160
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
165 170 175
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
180 185 190
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
195 200 205
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val
210 215 220
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
225 230 235 240
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
245 250 255
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
260 265 270
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
275 280 285
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
290 295 300
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
305 310 315 320
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
355 360 365
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
370 375 380
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
385 390 395 400
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
405 410 415
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn
420 425 430
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
435 440 445
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
450 455 460
Ser Pro Gly Lys
465
<210> 22
<211> 1407
<212> DNA
<213> Mus musculus
<400> 22
atgggatgga actggatctt tctcttcctc ttgtcaggaa ctgcaggtgt ctactctgag 60
gtccagctgc aacaatctgg acctgagctg gtgaagcctg ggacttcagt gaagatgtcc 120
tgtaaggctt ctggatacac attcactgac tgctacatga actgggtgaa gcagagccat 180
gggaagagcc ttgaatggat tggagatatt aatcctttca acggtggtac tacctacaac 240
cagaagttca agggcaaggc cacattgact gtagacaaat cctccagcac agcctacatg 300
cagctcaaca gcctgacatc tgacgactct gcagtctatt actgtgcaag atcccattat 360
tacttcgatg gtagagtccc ttgggatgct atggactact ggggtcaagg aacctcagtc 420
accgtctcct cagccaaaac gacaccccca tctgtctatc cactggcccc tggatctgct 480
gcccaaacta actccatggt gaccctggga tgcctggtca agggctattt ccctgagcca 540
gtgacagtga cctggaactc tggatccctg tccagcggtg tgcacacctt cccagctgtc 600
ctgcagtctg acctctacac tctgagcagc tcagtgactg tcccctccag cacctggccc 660
agcgagaccg tcacctgcaa cgttgcccac ccggccagca gcaccaaggt ggacaagaaa 720
attgtgccca gggattgtgg ttgtaagcct tgcatatgta cagtcccaga agtatcatct 780
gtcttcatct tccccccaaa gcccaaggat gtgctcacca ttactctgac tcctaaggtc 840
acgtgtgttg tggtagacat cagcaaggat gatcccgagg tccagttcag ctggtttgta 900
gatgatgtgg aggtgcacac agctcagacg caaccccggg aggagcagtt caacagcact 960
ttccgctcag tcagtgaact tcccatcatg caccaggact ggctcaatgg caaggagttc 1020
aaatgcaggg tcaacagtgc agctttccct gcccccatcg agaaaaccat ctccaaaacc 1080
aaaggcagac cgaaggctcc acaggtgtac accattccac ctcccaagga gcagatggcc 1140
aaggataaag tcagtctgac ctgcatgata acagacttct tccctgaaga cattactgtg 1200
gagtggcagt ggaatgggca gccagcggag aactacaaga acactcagcc catcatggac 1260
acagatggct cttacttcat ctacagcaag ctcaatgtgc agaagagcaa ctgggaggca 1320
ggaaatactt tcacctgctc tgtgttacat gagggcctgc acaaccacca tactgagaag 1380
agcctctccc actctcctgg taaatga 1407
<210> 23
<211> 217
<212> PRT
<213> 兔-小鼠嵌合体
<400> 23
Ala Gln Val Leu Thr Gln Thr Pro Ala Ser Val Ser Ala Ala Val Gly
1 5 10 15
Gly Thr Val Thr Ile Asn Cys Gln Ser Ser Gln Ser Val Tyr Asp Asn
20 25 30
Asn Trp Leu Ala Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
35 40 45
Leu Ile Tyr Asp Ala Ser Asp Leu Ala Ser Gly Val Pro Ser Arg Phe
50 55 60
Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr Leu Thr Ile Ser Gly Val
65 70 75 80
Gln Cys Ala Asp Ala Ala Thr Tyr Tyr Cys Gln Gly Ala Tyr Asn Asp
85 90 95
Val Ile Tyr Ala Phe Gly Gly Gly Thr Glu Val Val Val Lys Arg Thr
100 105 110
Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu
115 120 125
Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro
130 135 140
Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn
145 150 155 160
Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr
165 170 175
Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His
180 185 190
Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile
195 200 205
Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 24
<211> 654
<212> DNA
<213> 兔-小鼠嵌合体
<400> 24
gcgcaagtgc tgacccagac tccagcctcc gtgtctgcag ctgtgggagg cacagtcacc 60
atcaattgcc agtccagtca gagtgtttat gataacaact ggttagcctg gtttcagcag 120
aaaccagggc agcctcccaa gctcctgatt tatgatgcat ccgatctggc atctggggtc 180
ccatcgcggt tcagtggcag tggatctggg acacagttca ctctcaccat cagcggcgtg 240
cagtgtgccg atgctgccac ttactactgt caaggcgctt ataatgatgt tatttatgct 300
ttcggcggag ggaccgaggt ggtggtcaaa cgtacggatg ctgcaccaac tgtatccatc 360
ttcccaccat ccagtgagca gttaacatct ggaggtgcct cagtcgtgtg cttcttgaac 420
aacttctacc ccaaagacat caatgtcaag tggaagattg atggcagtga acgacaaaat 480
ggcgtcctga acagttggac tgatcaggac agcaaagaca gcacctacag catgagcagc 540
accctcacgt tgaccaagga cgagtatgaa cgacataaca gctatacctg tgaggccact 600
cacaagacat caacttcacc cattgtcaag agcttcaaca ggaatgagtg ttag 654
<210> 25
<211> 239
<212> PRT
<213> 兔-小鼠嵌合体
<400> 25
Met Asp Thr Arg Ala Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Thr Phe Ala Gln Val Leu Thr Gln Thr Pro Ala Ser
20 25 30
Val Ser Ala Ala Val Gly Gly Thr Val Thr Ile Asn Cys Gln Ser Ser
35 40 45
Gln Ser Val Tyr Asp Asn Asn Trp Leu Ala Trp Phe Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asp Leu Ala Ser
65 70 75 80
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Gln Phe Thr
85 90 95
Leu Thr Ile Ser Gly Val Gln Cys Ala Asp Ala Ala Thr Tyr Tyr Cys
100 105 110
Gln Gly Ala Tyr Asn Asp Val Ile Tyr Ala Phe Gly Gly Gly Thr Glu
115 120 125
Val Val Val Lys Arg Thr Asp Ala Ala Pro Thr Val Ser Ile Phe Pro
130 135 140
Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe
145 150 155 160
Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp
165 170 175
Gly Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp
180 185 190
Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys
195 200 205
Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys
210 215 220
Thr Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 26
<211> 720
<212> DNA
<213> 兔-小鼠嵌合体
<400> 26
atggacacga gggcccccac tcagctgctg gggctcctgc tgctctggct cccaggtgcc 60
acatttgcgc aagtgctgac ccagactcca gcctccgtgt ctgcagctgt gggaggcaca 120
gtcaccatca attgccagtc cagtcagagt gtttatgata acaactggtt agcctggttt 180
cagcagaaac cagggcagcc tcccaagctc ctgatttatg atgcatccga tctggcatct 240
ggggtcccat cgcggttcag tggcagtgga tctgggacac agttcactct caccatcagc 300
ggcgtgcagt gtgccgatgc tgccacttac tactgtcaag gcgcttataa tgatgttatt 360
tatgctttcg gcggagggac cgaggtggtg gtcaaacgta cggatgctgc accaactgta 420
tccatcttcc caccatccag tgagcagtta acatctggag gtgcctcagt cgtgtgcttc 480
ttgaacaact tctaccccaa agacatcaat gtcaagtgga agattgatgg cagtgaacga 540
caaaatggcg tcctgaacag ttggactgat caggacagca aagacagcac ctacagcatg 600
agcagcaccc tcacgttgac caaggacgag tatgaacgac ataacagcta tacctgtgag 660
gccactcaca agacatcaac ttcacccatt gtcaagagct tcaacaggaa tgagtgttag 720
<210> 27
<211> 433
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 27
Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro Gly Thr Pro
1 5 10 15
Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser Ser Tyr Trp
20 25 30
Met Asn Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Ile Gly
35 40 45
Thr Ile Asp Ser Gly Gly Arg Thr Asp Tyr Ala Ser Trp Ala Lys Gly
50 55 60
Arg Phe Thr Ile Ser Arg Thr Ser Thr Thr Met Asp Leu Lys Met Thr
65 70 75 80
Ser Leu Thr Thr Gly Asp Thr Ala Arg Tyr Phe Cys Ala Arg Asn Trp
85 90 95
Asn Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
100 105 110
Lys Gly Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr
115 120 125
Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu
130 135 140
Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His
145 150 155 160
Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser
165 170 175
Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn
180 185 190
Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro
195 200 205
Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser
210 215 220
Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr
225 230 235 240
Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp
245 250 255
Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr
260 265 270
Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser
275 280 285
Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu
290 295 300
Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys
305 310 315 320
Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr
325 330 335
Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr
340 345 350
Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln
355 360 365
Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met
370 375 380
Asn Thr Asn Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys
385 390 395 400
Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu
405 410 415
Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly
420 425 430
Lys
<210> 28
<211> 1302
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体
<400> 28
cagtcgctgg aggagtccgg gggtcgcctg gtcacgcctg ggacacccct gacactcacc 60
tgcacagcct ctggattctc cctcagtagt tattggatga actgggtccg ccaggctcca 120
ggggaggggc tggaatggat cggaaccatt gattctggtg gtaggacgga ctacgcgagc 180
tgggcaaaag gccgattcac catctccaga acctcgacta cgatggatct gaaaatgacc 240
agtctgacga ccggggacac ggcccgttat ttctgtgcca gaaattggaa cttgtggggc 300
caaggcaccc tcgtcaccgt ctcgagcgct tctacaaagg gcccatctgt ctatccactg 360
gcccctggat ctgctgccca aactaactcc atggtgaccc tgggatgcct ggtcaagggc 420
tatttccctg agccagtgac agtgacctgg aactctggat ccctgtccag cggtgtgcac 480
accttcccag ctgtcctgca gtctgacctc tacactctga gcagctcagt gactgtcccc 540
tccagcacct ggcccagcga gaccgtcacc tgcaacgttg cccacccggc cagcagcacc 600
aaggtggaca agaaaattgt gcccagggat tgtggttgta agccttgcat atgtacagtc 660
ccagaagtat catctgtctt catcttcccc ccaaagccca aggatgtgct caccattact 720
ctgactccta aggtcacgtg tgttgtggta gacatcagca aggatgatcc cgaggtccag 780
ttcagctggt ttgtagatga tgtggaggtg cacacagctc agacgcaacc ccgggaggag 840
cagttcaaca gcactttccg ctcagtcagt gaacttccca tcatgcacca ggactggctc 900
aatggcaagg agttcaaatg cagggtcaac agtgcagctt tccctgcccc catcgagaaa 960
accatctcca aaaccaaagg cagaccgaag gctccacagg tgtacaccat tccacctccc 1020
aaggagcaga tggccaagga taaagtcagt ctgacctgca tgataacaga cttcttccct 1080
gaagacatta ctgtggagtg gcagtggaat gggcagccag cggagaacta caagaacact 1140
cagcccatca tggacacaga tggctcttac ttcgtctaca gcaagctcaa tgtgcagaag 1200
agcaactggg aggcaggaaa tactttcacc tgctctgtgt tacatgaggg cctgcacaac 1260
caccatactg agaagagcct ctcccactct cctggtaaat ga 1302
<210> 29
<211> 452
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体
<400> 29
Met Glu Thr Gly Leu Arg Trp Leu Leu Leu Val Ala Val Leu Lys Gly
1 5 10 15
Val His Cys Gln Ser Leu Glu Glu Ser Gly Gly Arg Leu Val Thr Pro
20 25 30
Gly Thr Pro Leu Thr Leu Thr Cys Thr Ala Ser Gly Phe Ser Leu Ser
35 40 45
Ser Tyr Trp Met Asn Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu
50 55 60
Trp Ile Gly Thr Ile Asp Ser Gly Gly Arg Thr Asp Tyr Ala Ser Trp
65 70 75 80
Ala Lys Gly Arg Phe Thr Ile Ser Arg Thr Ser Thr Thr Met Asp Leu
85 90 95
Lys Met Thr Ser Leu Thr Thr Gly Asp Thr Ala Arg Tyr Phe Cys Ala
100 105 110
Arg Asn Trp Asn Leu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 125
Ala Ser Thr Lys Gly Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
130 135 140
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
145 150 155 160
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
165 170 175
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
180 185 190
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val
195 200 205
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
210 215 220
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
225 230 235 240
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
245 250 255
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
260 265 270
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
275 280 285
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
290 295 300
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
305 310 315 320
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
325 330 335
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
340 345 350
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
355 360 365
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
370 375 380
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
385 390 395 400
Pro Ile Met Asn Thr Asn Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
405 410 415
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
420 425 430
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
435 440 445
Ser Pro Gly Lys
450
<210> 30
<211> 1359
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体
<400> 30
atggagactg ggctgcgctg gcttctcctg gtcgctgtgc tcaaaggtgt ccactgtcag 60
tcgctggagg agtccggggg tcgcctggtc acgcctggga cacccctgac actcacctgc 120
acagcctctg gattctccct cagtagttat tggatgaact gggtccgcca ggctccaggg 180
gaggggctgg aatggatcgg aaccattgat tctggtggta ggacggacta cgcgagctgg 240
gcaaaaggcc gattcaccat ctccagaacc tcgactacga tggatctgaa aatgaccagt 300
ctgacgaccg gggacacggc ccgttatttc tgtgccagaa attggaactt gtggggccaa 360
ggcaccctcg tcaccgtctc gagcgcttct acaaagggcc catctgtcta tccactggcc 420
cctggatctg ctgcccaaac taactccatg gtgaccctgg gatgcctggt caagggctat 480
ttccctgagc cagtgacagt gacctggaac tctggatccc tgtccagcgg tgtgcacacc 540
ttcccagctg tcctgcagtc tgacctctac actctgagca gctcagtgac tgtcccctcc 600
agcacctggc ccagcgagac cgtcacctgc aacgttgccc acccggccag cagcaccaag 660
gtggacaaga aaattgtgcc cagggattgt ggttgtaagc cttgcatatg tacagtccca 720
gaagtatcat ctgtcttcat cttcccccca aagcccaagg atgtgctcac cattactctg 780
actcctaagg tcacgtgtgt tgtggtagac atcagcaagg atgatcccga ggtccagttc 840
agctggtttg tagatgatgt ggaggtgcac acagctcaga cgcaaccccg ggaggagcag 900
ttcaacagca ctttccgctc agtcagtgaa cttcccatca tgcaccagga ctggctcaat 960
ggcaaggagt tcaaatgcag ggtcaacagt gcagctttcc ctgcccccat cgagaaaacc 1020
atctccaaaa ccaaaggcag accgaaggct ccacaggtgt acaccattcc acctcccaag 1080
gagcagatgg ccaaggataa agtcagtctg acctgcatga taacagactt cttccctgaa 1140
gacattactg tggagtggca gtggaatggg cagccagcgg agaactacaa gaacactcag 1200
cccatcatgg acacagatgg ctcttacttc gtctacagca agctcaatgt gcagaagagc 1260
aactgggagg caggaaatac tttcacctgc tctgtgttac atgagggcct gcacaaccac 1320
catactgaga agagcctctc ccactctcct ggtaaatga 1359
<210> 31
<211> 213
<212> PRT
<213> Mus musculus
<400> 31
Gln Ile Val Leu Thr Gln Ser Pro Thr Ile Val Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Leu Ile Cys Ser Ala Ser Ser Ser Val Ser Phe Val
20 25 30
Asp Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Arg Trp Ile Tyr
35 40 45
Arg Thr Ser Asn Leu Gly Phe Gly Val Pro Ala Arg Phe Ser Gly Gly
50 55 60
Gly Ser Gly Thr Ser His Ser Leu Thr Ile Ser Arg Met Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Thr Tyr Pro Pro Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 32
<211> 642
<212> DNA
<213> Mus musculus
<400> 32
caaattgttc tcacccagtc tccaacaatc gtgtctgcat ctccagggga gaaggtcacc 60
ctaatctgca gtgccagttc aagtgtaagt ttcgtggact ggttccagca gaagccaggc 120
acttctccca aacgctggat ttacagaaca tccaacctgg gttttggagt ccctgctcgc 180
ttcagtggcg gtggatctgg gacctctcac tctctcacaa tcagccgaat ggaggctgaa 240
gatgctgcca cttattactg ccagcaaagg agtacttacc cacccacgtt cggtgctggg 300
accaagctgg aactgaaacg ggctgatgct gcaccaactg tatccatctt cccaccatcc 360
agtgagcagt taacatctgg aggtgcctca gtcgtgtgct tcttgaacaa cttctacccc 420
aaagacatca atgtcaagtg gaagattgat ggcagtgaac gacaaaatgg cgtcctgaac 480
agttggactg atcaggacag caaagacagc acctacagca tgagcagcac cctcacgttg 540
accaaggacg agtatgaacg acataacagc tatacctgtg aggccactca caagacatca 600
acttcaccca ttgtcaagag cttcaacagg aatgagtgtt ag 642
<210> 33
<211> 235
<212> PRT
<213> Mus musculus
<400> 33
Met His Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Val Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Thr Ile
20 25 30
Val Ser Ala Ser Pro Gly Glu Lys Val Thr Leu Ile Cys Ser Ala Ser
35 40 45
Ser Ser Val Ser Phe Val Asp Trp Phe Gln Gln Lys Pro Gly Thr Ser
50 55 60
Pro Lys Arg Trp Ile Tyr Arg Thr Ser Asn Leu Gly Phe Gly Val Pro
65 70 75 80
Ala Arg Phe Ser Gly Gly Gly Ser Gly Thr Ser His Ser Leu Thr Ile
85 90 95
Ser Arg Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg
100 105 110
Ser Thr Tyr Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
115 120 125
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
130 135 140
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
145 150 155 160
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
165 170 175
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
195 200 205
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
210 215 220
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 34
<211> 708
<212> DNA
<213> Mus musculus
<400> 34
atgcattttc aagtgcagat tttcagcttc ctgctaatca gtgcctcagt catagtgtcc 60
agagggcaaa ttgttctcac ccagtctcca acaatcgtgt ctgcatctcc aggggagaag 120
gtcaccctaa tctgcagtgc cagttcaagt gtaagtttcg tggactggtt ccagcagaag 180
ccaggcactt ctcccaaacg ctggatttac agaacatcca acctgggttt tggagtccct 240
gctcgcttca gtggcggtgg atctgggacc tctcactctc tcacaatcag ccgaatggag 300
gctgaagatg ctgccactta ttactgccag caaaggagta cttacccacc cacgttcggt 360
gctgggacca agctggaact gaaacgggct gatgctgcac caactgtatc catcttccca 420
ccatccagtg agcagttaac atctggaggt gcctcagtcg tgtgcttctt gaacaacttc 480
taccccaaag acatcaatgt caagtggaag attgatggca gtgaacgaca aaatggcgtc 540
ctgaacagtt ggactgatca ggacagcaaa gacagcacct acagcatgag cagcaccctc 600
acgttgacca aggacgagta tgaacgacat aacagctata cctgtgaggc cactcacaag 660
acatcaactt cacccattgt caagagcttc aacaggaatg agtgttag 708
<210> 35
<211> 449
<212> PRT
<213> Mus musculus
<400> 35
Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Pro Ser Gln
1 5 10 15
Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser
20 25 30
Gly Met Gly Val Gly Trp Ile Arg His Pro Ser Gly Lys Asn Leu Glu
35 40 45
Trp Leu Ala His Ile Trp Trp Asp Asp Val Lys Arg Tyr Asn Pro Val
50 55 60
Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn Ser Gln Val
65 70 75 80
Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr
85 90 95
Cys Ala Arg Ile Glu Asp Phe Asp Tyr Asp Glu Glu Tyr Tyr Ala Met
100 105 110
Asp Tyr Trp Gly Gln Gly Thr Ser Val Ile Val Ser Ser Ala Lys Thr
115 120 125
Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr
130 135 140
Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser
180 185 190
Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn
195 200 205
Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro
210 215 220
Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser
225 230 235 240
Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr
245 250 255
Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp
260 265 270
Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr
275 280 285
Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser
290 295 300
Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr
340 345 350
Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr
355 360 365
Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln
370 375 380
Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met
385 390 395 400
Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys
405 410 415
Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu
420 425 430
Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly
435 440 445
Lys
<210> 36
<211> 1350
<212> DNA
<213> Mus musculus
<400> 36
caggttactc tgaaagagtc tggccctggg atattgcagc cctcccagac cctcagtctg 60
acttgttctt tctctgggtt ttcactgagc acttctggta tgggtgtagg ctggattcgt 120
cacccatcag ggaagaatct ggagtggctg gcacacattt ggtgggatga tgtcaagcgc 180
tataacccag tcctgaagag ccgactgact atctccaagg atacctccaa cagccaggta 240
ttcctcaaga tcgccaatgt ggacactgca gatactgcca catactactg tgctcgaata 300
gaggactttg attacgacga ggagtattat gctatggact actggggtca aggaacctca 360
gtcatcgtct cctcagccaa aacgacaccc ccatctgtct atccactggc ccctggatct 420
gctgcccaaa ctaactccat ggtgaccctg ggatgcctgg tcaagggcta tttccctgag 480
ccagtgacag tgacctggaa ctctggatcc ctgtccagcg gtgtgcacac cttcccagct 540
gtcctgcagt ctgacctcta cactctgagc agctcagtga ctgtcccctc cagcacctgg 600
cccagcgaga ccgtcacctg caacgttgcc cacccggcca gcagcaccaa ggtggacaag 660
aaaattgtgc ccagggattg tggttgtaag ccttgcatat gtacagtccc agaagtatca 720
tctgtcttca tcttcccccc aaagcccaag gatgtgctca ccattactct gactcctaag 780
gtcacgtgtg ttgtggtaga catcagcaag gatgatcccg aggtccagtt cagctggttt 840
gtagatgatg tggaggtgca cacagctcag acgcaacccc gggaggagca gttcaacagc 900
actttccgct cagtcagtga acttcccatc atgcaccagg actggctcaa tggcaaggag 960
ttcaaatgca gggtcaacag tgcagctttc cctgccccca tcgagaaaac catctccaaa 1020
accaaaggca gaccgaaggc tccacaggtg tacaccattc cacctcccaa ggagcagatg 1080
gccaaggata aagtcagtct gacctgcatg ataacagact tcttccctga agacattact 1140
gtggagtggc agtggaatgg gcagccagcg gagaactaca agaacactca gcccatcatg 1200
gacacagatg gctcttactt cgtctacagc aagctcaatg tgcagaagag caactgggag 1260
gcaggaaata ctttcacctg ctctgtgtta catgagggcc tgcacaacca ccatactgag 1320
aagagcctct cccactctcc tggtaaatga 1350
<210> 37
<211> 468
<212> PRT
<213> Mus musculus
<400> 37
Met Gly Arg Leu Thr Ser Ser Phe Leu Leu Leu Ile Val Pro Ala Tyr
1 5 10 15
Val Leu Ser Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln
20 25 30
Pro Ser Gln Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu
35 40 45
Ser Thr Ser Gly Met Gly Val Gly Trp Ile Arg His Pro Ser Gly Lys
50 55 60
Asn Leu Glu Trp Leu Ala His Ile Trp Trp Asp Asp Val Lys Arg Tyr
65 70 75 80
Asn Pro Val Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Asn
85 90 95
Ser Gln Val Phe Leu Lys Ile Ala Asn Val Asp Thr Ala Asp Thr Ala
100 105 110
Thr Tyr Tyr Cys Ala Arg Ile Glu Asp Phe Asp Tyr Asp Glu Glu Tyr
115 120 125
Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Ile Val Ser Ser
130 135 140
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
145 150 155 160
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
165 170 175
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
180 185 190
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
195 200 205
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val
210 215 220
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
225 230 235 240
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
245 250 255
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
260 265 270
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
275 280 285
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
290 295 300
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
305 310 315 320
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
355 360 365
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
370 375 380
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
385 390 395 400
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
405 410 415
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
420 425 430
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
435 440 445
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
450 455 460
Ser Pro Gly Lys
465
<210> 38
<211> 1407
<212> DNA
<213> Mus musculus
<400> 38
atgggcaggc ttacttcttc attcctgcta ctgattgtcc ctgcatatgt cctgtcccag 60
gttactctga aagagtctgg ccctgggata ttgcagccct cccagaccct cagtctgact 120
tgttctttct ctgggttttc actgagcact tctggtatgg gtgtaggctg gattcgtcac 180
ccatcaggga agaatctgga gtggctggca cacatttggt gggatgatgt caagcgctat 240
aacccagtcc tgaagagccg actgactatc tccaaggata cctccaacag ccaggtattc 300
ctcaagatcg ccaatgtgga cactgcagat actgccacat actactgtgc tcgaatagag 360
gactttgatt acgacgagga gtattatgct atggactact ggggtcaagg aacctcagtc 420
atcgtctcct cagccaaaac gacaccccca tctgtctatc cactggcccc tggatctgct 480
gcccaaacta actccatggt gaccctggga tgcctggtca agggctattt ccctgagcca 540
gtgacagtga cctggaactc tggatccctg tccagcggtg tgcacacctt cccagctgtc 600
ctgcagtctg acctctacac tctgagcagc tcagtgactg tcccctccag cacctggccc 660
agcgagaccg tcacctgcaa cgttgcccac ccggccagca gcaccaaggt ggacaagaaa 720
attgtgccca gggattgtgg ttgtaagcct tgcatatgta cagtcccaga agtatcatct 780
gtcttcatct tccccccaaa gcccaaggat gtgctcacca ttactctgac tcctaaggtc 840
acgtgtgttg tggtagacat cagcaaggat gatcccgagg tccagttcag ctggtttgta 900
gatgatgtgg aggtgcacac agctcagacg caaccccggg aggagcagtt caacagcact 960
ttccgctcag tcagtgaact tcccatcatg caccaggact ggctcaatgg caaggagttc 1020
aaatgcaggg tcaacagtgc agctttccct gcccccatcg agaaaaccat ctccaaaacc 1080
aaaggcagac cgaaggctcc acaggtgtac accattccac ctcccaagga gcagatggcc 1140
aaggataaag tcagtctgac ctgcatgata acagacttct tccctgaaga cattactgtg 1200
gagtggcagt ggaatgggca gccagcggag aactacaaga acactcagcc catcatggac 1260
acagatggct cttacttcgt ctacagcaag ctcaatgtgc agaagagcaa ctgggaggca 1320
ggaaatactt tcacctgctc tgtgttacat gagggcctgc acaaccacca tactgagaag 1380
agcctctccc actctcctgg taaatga 1407
<210> 39
<211> 5
<212> PRT
<213> Mus musculus
<400> 39
Asp His Tyr Met Ser
1 5
<210> 40
<211> 17
<212> PRT
<213> Mus musculus
<400> 40
Asp Ile Asn Pro Tyr Ser Gly Glu Thr Thr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 41
<211> 10
<212> PRT
<213> Mus musculus
<400> 41
Asp Asp Tyr Asp Ala Ser Pro Phe Ala Tyr
1 5 10
<210> 42
<211> 11
<212> PRT
<213> Mus musculus
<400> 42
Gln Ala Ser Gln Gly Thr Ser Ile Asn Leu Asn
1 5 10
<210> 43
<211> 7
<212> PRT
<213> Mus musculus
<400> 43
Gly Ser Ser Asn Leu Glu Asp
1 5
<210> 44
<211> 9
<212> PRT
<213> Mus musculus
<400> 44
Leu Gln His Ser Tyr Leu Pro Tyr Thr
1 5
<210> 45
<211> 5
<212> PRT
<213> Mus musculus
<400> 45
Asp Cys Tyr Met Asn
1 5
<210> 46
<211> 17
<212> PRT
<213> Mus musculus
<400> 46
Asp Ile Asn Pro Phe Asn Gly Gly Thr Thr Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 47
<211> 16
<212> PRT
<213> Mus musculus
<400> 47
Ser His Tyr Tyr Phe Asp Gly Arg Val Pro Trp Asp Ala Met Asp Tyr
1 5 10 15
<210> 48
<211> 15
<212> PRT
<213> Mus musculus
<400> 48
Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn
1 5 10 15
<210> 49
<211> 7
<212> PRT
<213> Mus musculus
<400> 49
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 50
<211> 9
<212> PRT
<213> Mus musculus
<400> 50
Gln Gln Ser Asn Glu Asp Pro Trp Thr
1 5
<210> 51
<211> 5
<212> PRT
<213> 兔-小鼠嵌合体
<400> 51
Ser Tyr Trp Met Asn
1 5
<210> 52
<211> 16
<212> PRT
<213> 兔-小鼠嵌合体
<400> 52
Thr Ile Asp Ser Gly Gly Arg Thr Asp Tyr Ala Ser Trp Ala Lys Gly
1 5 10 15
<210> 53
<211> 4
<212> PRT
<213> 兔-小鼠嵌合体
<400> 53
Asn Trp Asn Leu
1
<210> 54
<211> 13
<212> PRT
<213> 兔-小鼠嵌合体
<400> 54
Gln Ser Ser Gln Ser Val Tyr Asp Asn Asn Trp Leu Ala
1 5 10
<210> 55
<211> 7
<212> PRT
<213> 兔-小鼠嵌合体
<400> 55
Asp Ala Ser Asp Leu Ala Ser
1 5
<210> 56
<211> 10
<212> PRT
<213> 兔-小鼠嵌合体
<400> 56
Gln Gly Ala Tyr Asn Asp Val Ile Tyr Ala
1 5 10
<210> 57
<211> 7
<212> PRT
<213> Mus musculus
<400> 57
Thr Ser Gly Met Gly Val Gly
1 5
<210> 58
<211> 16
<212> PRT
<213> Mus musculus
<400> 58
His Ile Trp Trp Asp Asp Val Lys Arg Tyr Asn Pro Val Leu Lys Ser
1 5 10 15
<210> 59
<211> 14
<212> PRT
<213> Mus musculus
<400> 59
Glu Asp Phe Asp Tyr Asp Glu Glu Tyr Tyr Ala Met Asp Tyr
1 5 10
<210> 60
<211> 10
<212> PRT
<213> Mus musculus
<400> 60
Ser Ala Ser Ser Ser Val Ser Phe Val Asp
1 5 10
<210> 61
<211> 7
<212> PRT
<213> Mus musculus
<400> 61
Arg Thr Ser Asn Leu Gly Phe
1 5
<210> 62
<211> 9
<212> PRT
<213> Mus musculus
<400> 62
Gln Gln Arg Ser Thr Tyr Pro Pro Thr
1 5
<210> 63
<211> 20
<212> PRT
<213> 智人
<400> 63
Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp
1 5 10 15
Trp Arg Pro Ser
20
<210> 64
<211> 20
<212> PRT
<213> 智人
<400> 64
Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp
1 5 10 15
Arg Pro Ser Gly
20
<210> 65
<211> 20
<212> PRT
<213> 智人
<400> 65
Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg
1 5 10 15
Pro Ser Gly Pro
20
<210> 66
<211> 20
<212> PRT
<213> 智人
<400> 66
Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro
1 5 10 15
Ser Gly Pro Asp
20
<210> 67
<211> 20
<212> PRT
<213> 智人
<400> 67
Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser
1 5 10 15
Gly Pro Asp Phe
20
<210> 68
<211> 20
<212> PRT
<213> 智人
<400> 68
Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser Gly
1 5 10 15
Pro Asp Phe Arg
20
<210> 69
<211> 20
<212> PRT
<213> 智人
<400> 69
Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser Gly Pro
1 5 10 15
Asp Phe Arg Cys
20
<210> 70
<211> 14
<212> PRT
<213> 智人
<400> 70
Ser Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys
1 5 10
<210> 71
<211> 7
<212> PRT
<213> 智人
<400> 71
Leu Val Ala Ser Cys Lys Cys
1 5
<210> 72
<211> 8
<212> PRT
<213> 智人
<400> 72
Cys Arg Glu Leu His Phe Thr Arg
1 5
<210> 73
<211> 7
<212> PRT
<213> 智人
<400> 73
Cys Ile Pro Asp Arg Tyr Arg
1 5
<210> 74
<211> 399
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 74
atggacacga gggcccccac tcagctgctg gggctcctgc tgctctggct cccaggtgcc 60
acatttgctc aagttctgac ccagagtcca agcagtctct ccgccagcgt aggcgatcgt 120
gtgactatta cctgtcaatc tagtcagagc gtgtatgata acaattggct ggcgtggtac 180
cagcaaaaac cgggcaaagc cccgaagctg ctcatctatg acgcgtccga tctggctagc 240
ggtgtgccaa gccgtttcag tggcagtggc agcggtactg actttaccct cacaatttcg 300
tctctccagc cggaagattt cgccacttac tattgtcaag gtgcttacaa cgatgtgatt 360
tatgccttcg gtcagggcac taaagtagaa atcaaacgt 399
<210> 75
<211> 133
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 75
Met Asp Thr Arg Ala Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Thr Phe Ala Gln Val Leu Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ser Ser
35 40 45
Gln Ser Val Tyr Asp Asn Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asp Leu Ala Ser
65 70 75 80
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
100 105 110
Gln Gly Ala Tyr Asn Asp Val Ile Tyr Ala Phe Gly Gln Gly Thr Lys
115 120 125
Val Glu Ile Lys Arg
130
<210> 76
<211> 393
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 76
atggagactg ggctgcgctg gcttctcctg gtcgctgtgc tcaaaggtgt ccactgtgag 60
gtgcagctgt tggagtctgg aggcgggctt gtccagcctg gagggagcct gcgtctctct 120
tgtgcagcaa gcggcttcag cttatcctct tactggatga attgggtgcg gcaggcacct 180
gggaagggcc tggagtgggt gggcaccatt gattccggag gccgtacaga ctacgcgtct 240
tgggcaaagg gccgtttcac catttcccgc gacaactcca aaaataccat gtacctccag 300
atgaactctc tccgcgcaga ggacacagca cgttattact gtgcacgcaa ctggaatctg 360
tggggtcaag gtactcttgt aacagtctcg agc 393
<210> 77
<211> 131
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 77
Met Glu Thr Gly Leu Arg Trp Leu Leu Leu Val Ala Val Leu Lys Gly
1 5 10 15
Val His Cys Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Leu
35 40 45
Ser Ser Tyr Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60
Glu Trp Val Gly Thr Ile Asp Ser Gly Gly Arg Thr Asp Tyr Ala Ser
65 70 75 80
Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
85 90 95
Met Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Arg Tyr
100 105 110
Tyr Cys Ala Arg Asn Trp Asn Leu Trp Gly Gln Gly Thr Leu Val Thr
115 120 125
Val Ser Ser
130
<210> 78
<211> 11
<212> PRT
<213> Mus musculus
<400> 78
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 79
<211> 7
<212> PRT
<213> Mus musculus
<400> 79
Tyr Thr Ser Arg Leu Leu Ser
1 5
<210> 80
<211> 9
<212> PRT
<213> Mus musculus
<400> 80
Gln Gln Gly Asp Thr Leu Pro Tyr Thr
1 5
<210> 81
<211> 11
<212> PRT
<213> Mus musculus
<400> 81
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 82
<211> 24
<212> PRT
<213> Rattus norvegicus
<400> 82
Gln Gly Trp Gln Ala Phe Lys Asn Asp Ala Thr Glu Ile Ile Pro Gly
1 5 10 15
Leu Arg Glu Tyr Pro Glu Pro Pro
20
<210> 83
<211> 20
<212> PRT
<213> Rattus norvegicus
<400> 83
Thr Glu Ile Ile Pro Gly Leu Arg Glu Tyr Pro Glu Pro Pro Gln Glu
1 5 10 15
Leu Glu Asn Asn
20
<210> 84
<211> 20
<212> PRT
<213> Rattus norvegicus
<400> 84
Pro Glu Pro Pro Gln Glu Leu Glu Asn Asn Gln Thr Met Asn Arg Ala
1 5 10 15
Glu Asn Gly Gly
20
<210> 85
<211> 20
<212> PRT
<213> Rattus norvegicus
<400> 85
Glu Asn Gly Gly Arg Pro Pro His His Pro Tyr Asp Thr Lys Asp Val
1 5 10 15
Ser Glu Tyr Ser
20
<210> 86
<211> 14
<212> PRT
<213> Rattus norvegicus
<400> 86
Cys Arg Glu Leu His Tyr Thr Arg Phe Val Thr Asp Gly Pro
1 5 10
<210> 87
<211> 25
<212> PRT
<213> Rattus norvegicus
<400> 87
Cys Arg Glu Leu His Tyr Thr Arg Phe Val Thr Asp Gly Pro Ser Arg
1 5 10 15
Ser Ala Lys Pro Val Thr Glu Leu Val
20 25
<210> 88
<211> 23
<212> PRT
<213> Rattus norvegicus
<400> 88
Cys Arg Ser Ala Lys Pro Val Thr Glu Leu Val Ser Ser Gly Gln Ser
1 5 10 15
Gly Pro Arg Ala Arg Leu Leu
20
<210> 89
<211> 25
<212> PRT
<213> Rattus norvegicus
<400> 89
Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Val Lys Trp
1 5 10 15
Trp Arg Pro Asn Gly Pro Asp Phe Arg
20 25
<210> 90
<211> 20
<212> PRT
<213> Rattus norvegicus
<400> 90
Arg Ala Gln Arg Val Gln Leu Leu Cys Pro Gly Gly Ala Ala Pro Arg
1 5 10 15
Ser Arg Lys Val
20
<210> 91
<211> 16
<212> PRT
<213> Rattus norvegicus
<400> 91
Pro Gly Gly Ala Ala Pro Arg Ser Arg Lys Val Arg Leu Val Ala Ser
1 5 10 15
<210> 92
<211> 23
<212> PRT
<213> Rattus norvegicus
<400> 92
Lys Arg Leu Thr Arg Phe His Asn Gln Ser Glu Leu Lys Asp Phe Gly
1 5 10 15
Pro Glu Thr Ala Arg Pro Gln
20
<210> 93
<211> 16
<212> PRT
<213> Rattus norvegicus
<400> 93
Ile Pro Asp Arg Tyr Ala Gln Arg Val Gln Leu Leu Ser Pro Gly Gly
1 5 10 15
<210> 94
<211> 24
<212> PRT
<213> Rattus norvegicus
<400> 94
Ser Glu Leu Lys Asp Phe Gly Pro Glu Thr Ala Arg Pro Gln Lys Gly
1 5 10 15
Arg Lys Pro Arg Pro Arg Ala Arg
20
<210> 95
<211> 23
<212> PRT
<213> Rattus norvegicus
<400> 95
Lys Gly Arg Lys Pro Arg Pro Arg Ala Arg Gly Ala Lys Ala Asn Gln
1 5 10 15
Ala Glu Leu Glu Asn Ala Tyr
20
<210> 96
<211> 18
<212> PRT
<213> Rattus norvegicus
<400> 96
Pro Asn Ala Ile Gly Arg Val Lys Trp Trp Arg Pro Asn Gly Pro Asp
1 5 10 15
Phe Arg
<210> 97
<211> 22
<212> PRT
<213> Rattus norvegicus
<400> 97
Lys Trp Trp Arg Pro Asn Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg
1 5 10 15
Tyr Arg Ala Gln Arg Val
20
<210> 98
<211> 213
<212> PRT
<213> Rattus norvegicus
<400> 98
Met Gln Leu Ser Leu Ala Pro Cys Leu Ala Cys Leu Leu Val His Ala
1 5 10 15
Ala Phe Val Ala Val Glu Ser Gln Gly Trp Gln Ala Phe Lys Asn Asp
20 25 30
Ala Thr Glu Ile Ile Pro Gly Leu Arg Glu Tyr Pro Glu Pro Pro Gln
35 40 45
Glu Leu Glu Asn Asn Gln Thr Met Asn Arg Ala Glu Asn Gly Gly Arg
50 55 60
Pro Pro His His Pro Tyr Asp Thr Lys Asp Val Ser Glu Tyr Ser Cys
65 70 75 80
Arg Glu Leu His Tyr Thr Arg Phe Val Thr Asp Gly Pro Cys Arg Ser
85 90 95
Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala
100 105 110
Arg Leu Leu Pro Asn Ala Ile Gly Arg Val Lys Trp Trp Arg Pro Asn
115 120 125
Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val
130 135 140
Gln Leu Leu Cys Pro Gly Gly Ala Ala Pro Arg Ser Arg Lys Val Arg
145 150 155 160
Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn Gln
165 170 175
Ser Glu Leu Lys Asp Phe Gly Pro Glu Thr Ala Arg Pro Gln Lys Gly
180 185 190
Arg Lys Pro Arg Pro Arg Ala Arg Gly Ala Lys Ala Asn Gln Ala Glu
195 200 205
Leu Glu Asn Ala Tyr
210
<210> 99
<211> 7
<212> PRT
<213> Mus musculus
<400> 99
Tyr Thr Ser Arg Leu His Ser
1 5
<210> 100
<211> 9
<212> PRT
<213> Mus musculus
<400> 100
Gln Gln Gly Asp Thr Leu Pro Tyr Thr
1 5
<210> 101
<211> 11
<212> PRT
<213> Mus musculus
<400> 101
Arg Ala Ser Gln Val Ile Thr Asn Tyr Leu Tyr
1 5 10
<210> 102
<211> 7
<212> PRT
<213> Mus musculus
<400> 102
Tyr Thr Ser Arg Leu His Ser
1 5
<210> 103
<211> 9
<212> PRT
<213> Mus musculus
<400> 103
Gln Gln Gly Asp Thr Leu Pro Tyr Thr
1 5
<210> 104
<211> 11
<212> PRT
<213> Mus musculus
<400> 104
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 105
<211> 7
<212> PRT
<213> Mus musculus
<400> 105
Tyr Thr Ser Arg Leu Leu Ser
1 5
<210> 106
<211> 9
<212> PRT
<213> Mus musculus
<400> 106
Gln Gln Gly Asp Thr Leu Pro Tyr Thr
1 5
<210> 107
<211> 11
<212> PRT
<213> Mus musculus
<400> 107
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 108
<211> 7
<212> PRT
<213> Mus musculus
<400> 108
Tyr Thr Ser Arg Leu Phe Ser
1 5
<210> 109
<211> 9
<212> PRT
<213> Mus musculus
<400> 109
Gln Gln Gly Asp Thr Leu Pro Tyr Thr
1 5
<210> 110
<211> 11
<212> PRT
<213> Mus musculus
<400> 110
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 111
<211> 7
<212> PRT
<213> Mus musculus
<400> 111
Tyr Thr Ser Arg Leu Leu Ser
1 5
<210> 112
<211> 9
<212> PRT
<213> Mus musculus
<400> 112
Gln Gln Gly Asp Thr Leu Pro Tyr Thr
1 5
<210> 113
<211> 11
<212> PRT
<213> Mus musculus
<400> 113
Arg Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn
1 5 10
<210> 114
<211> 7
<212> PRT
<213> Mus musculus
<400> 114
Tyr Thr Ser Thr Leu Gln Ser
1 5
<210> 115
<211> 9
<212> PRT
<213> Mus musculus
<400> 115
Gln Gln Gly Asp Thr Leu Pro Tyr Thr
1 5
<210> 116
<211> 12
<212> PRT
<213> Mus musculus
<400> 116
Ser Val Ser Ser Ser Ile Ser Ser Ser Asn Leu His
1 5 10
<210> 117
<211> 213
<212> PRT
<213> Mus musculus
<400> 117
Gln Ile Val Leu Ser Gln Ser Pro Ala Ile Leu Ser Thr Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Tyr Tyr Met
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Pro Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Thr Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asp Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 118
<211> 642
<212> DNA
<213> Mus musculus
<400> 118
caaattgttc tctcccagtc tccagcaatc ctgtctacat ctccagggga gaaggtcaca 60
atgacttgca gggccagctc aagtgtatat tacatgcact ggtaccagca gaagccagga 120
tcctccccca aaccctggat ttatgccaca tccaacctgg cttctggagt ccctgttcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcaccagagt ggaggctgaa 240
gatgctgcca cttattactg ccagcagtgg agtagtgacc cactcacgtt cggtgctggg 300
accaagctgg agctgaaacg ggctgatgct gcaccaactg tatccatctt cccaccatcc 360
agtgagcagt taacatctgg aggtgcctca gtcgtgtgct tcttgaacaa cttctacccc 420
aaagacatca atgtcaagtg gaagattgat ggcagtgaac gacaaaatgg cgtcctgaac 480
agttggactg atcaggacag caaagacagc acctacagca tgagcagcac cctcacgttg 540
accaaggacg agtatgaacg acataacagc tatacctgtg aggccactca caagacatca 600
acttcaccca ttgtcaagag cttcaacagg aatgagtgtt ag 642
<210> 119
<211> 235
<212> PRT
<213> Mus musculus
<400> 119
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Ile
20 25 30
Leu Ser Thr Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Tyr Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Lys Pro Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
85 90 95
Thr Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asp Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
115 120 125
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
130 135 140
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
145 150 155 160
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
165 170 175
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
195 200 205
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
210 215 220
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 120
<211> 708
<212> DNA
<213> Mus musculus
<400> 120
atggattttc aagtgcagat tttcagcttc ctgctaatca gtgcttcagt cattatgtcc 60
aggggacaaa ttgttctctc ccagtctcca gcaatcctgt ctacatctcc aggggagaag 120
gtcacaatga cttgcagggc cagctcaagt gtatattaca tgcactggta ccagcagaag 180
ccaggatcct cccccaaacc ctggatttat gccacatcca acctggcttc tggagtccct 240
gttcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcac cagagtggag 300
gctgaagatg ctgccactta ttactgccag cagtggagta gtgacccact cacgttcggt 360
gctgggacca agctggagct gaaacgggct gatgctgcac caactgtatc catcttccca 420
ccatccagtg agcagttaac atctggaggt gcctcagtcg tgtgcttctt gaacaacttc 480
taccccaaag acatcaatgt caagtggaag attgatggca gtgaacgaca aaatggcgtc 540
ctgaacagtt ggactgatca ggacagcaaa gacagcacct acagcatgag cagcaccctc 600
acgttgacca aggacgagta tgaacgacat aacagctata cctgtgaggc cactcacaag 660
acatcaactt cacccattgt caagagcttc aacaggaatg agtgttag 708
<210> 121
<211> 445
<212> PRT
<213> Mus musculus
<400> 121
Glu Val Gln Val Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Phe Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Leu Asp Pro Glu Asp Gly Glu Ser Asp Tyr Ala Pro Lys Phe
50 55 60
Gln Asp Lys Ala Ile Met Thr Ala Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Glu Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Phe Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
180 185 190
Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
210 215 220
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
245 250 255
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln
260 265 270
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
290 295 300
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
305 310 315 320
Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
340 345 350
Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
355 360 365
Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
370 375 380
Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly
385 390 395 400
Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu
405 410 415
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
420 425 430
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 122
<211> 1338
<212> DNA
<213> Mus musculus
<400> 122
gaggttcagg tgcagcagtc tgggccagaa cttgtgaagc caggggcctc agtcaagttg 60
tcctgcacag cttctggctt caacattaaa gactacttta tacactgggt gaagcagagg 120
cctgaacagg gcctggagtg gattggaagg cttgatcctg aggatggtga aagtgattat 180
gccccgaagt tccaggacaa ggccattatg acagcagaca catcatccaa cacagcctat 240
cttcagctca gaagcctgac atctgaggac actgccatct attattgtga gagagaggac 300
tacgatggta cctacacctt ttttccttac tggggccaag ggactctggt cactgtctct 360
gcagccaaaa cgacaccccc atctgtctat ccactggccc ctggatctgc tgcccaaact 420
aactccatgg tgaccctggg atgcctggtc aagggctatt tccctgagcc agtgacagtg 480
acctggaact ctggatccct gtccagcggt gtgcacacct tcccagctgt cctgcagtct 540
gacctctaca ctctgagcag ctcagtgact gtcccctcca gcacctggcc cagcgagacc 600
gtcacctgca acgttgccca cccggccagc agcaccaagg tggacaagaa aattgtgccc 660
agggattgtg gttgtaagcc ttgcatatgt acagtcccag aagtatcatc tgtcttcatc 720
ttccccccaa agcccaagga tgtgctcacc attactctga ctcctaaggt cacgtgtgtt 780
gtggtagaca tcagcaagga tgatcccgag gtccagttca gctggtttgt agatgatgtg 840
gaggtgcaca cagctcagac gcaaccccgg gaggagcagt tcaacagcac tttccgctca 900
gtcagtgaac ttcccatcat gcaccaggac tggctcaatg gcaaggagtt caaatgcagg 960
gtcaacagtg cagctttccc tgcccccatc gagaaaacca tctccaaaac caaaggcaga 1020
ccgaaggctc cacaggtgta caccattcca cctcccaagg agcagatggc caaggataaa 1080
gtcagtctga cctgcatgat aacagacttc ttccctgaag acattactgt ggagtggcag 1140
tggaatgggc agccagcgga gaactacaag aacactcagc ccatcatgga cacagatggc 1200
tcttacttca tctacagcaa gctcaatgtg cagaagagca actgggaggc aggaaatact 1260
ttcacctgct ctgtgttaca tgagggcctg cacaaccacc atactgagaa gagcctctcc 1320
cactctcctg gtaaatga 1338
<210> 123
<211> 464
<212> PRT
<213> Mus musculus
<400> 123
Met Lys Cys Ser Trp Val Ile Phe Phe Leu Met Ala Val Val Thr Gly
1 5 10 15
Val Asn Ser Glu Val Gln Val Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile
35 40 45
Lys Asp Tyr Phe Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu
50 55 60
Glu Trp Ile Gly Arg Leu Asp Pro Glu Asp Gly Glu Ser Asp Tyr Ala
65 70 75 80
Pro Lys Phe Gln Asp Lys Ala Ile Met Thr Ala Asp Thr Ser Ser Asn
85 90 95
Thr Ala Tyr Leu Gln Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Ile
100 105 110
Tyr Tyr Cys Glu Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Phe Phe Pro
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr
130 135 140
Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn
145 150 155 160
Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val
195 200 205
Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val
210 215 220
Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg
225 230 235 240
Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser
245 250 255
Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu
260 265 270
Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro
275 280 285
Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala
290 295 300
Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val
305 310 315 320
Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe
325 330 335
Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr
340 345 350
Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile
355 360 365
Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys
370 375 380
Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp
385 390 395 400
Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp
405 410 415
Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser
420 425 430
Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly
435 440 445
Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 124
<211> 1395
<212> DNA
<213> Mus musculus
<400> 124
atgaaatgca gctgggtcat cttcttcctg atggcagtgg ttacaggggt caattcagag 60
gttcaggtgc agcagtctgg gccagaactt gtgaagccag gggcctcagt caagttgtcc 120
tgcacagctt ctggcttcaa cattaaagac tactttatac actgggtgaa gcagaggcct 180
gaacagggcc tggagtggat tggaaggctt gatcctgagg atggtgaaag tgattatgcc 240
ccgaagttcc aggacaaggc cattatgaca gcagacacat catccaacac agcctatctt 300
cagctcagaa gcctgacatc tgaggacact gccatctatt attgtgagag agaggactac 360
gatggtacct acaccttttt tccttactgg ggccaaggga ctctggtcac tgtctctgca 420
gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 480
tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 540
tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 600
ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 660
acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 720
gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 780
cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 840
gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 900
gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 960
agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 1020
aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 1080
aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 1140
agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 1200
aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 1260
tacttcatct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 1320
acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 1380
tctcctggta aatga 1395
<210> 125
<211> 215
<212> PRT
<213> Mus musculus
<400> 125
Glu Ile Val Leu Thr Gln Ser Pro Ala Leu Met Ala Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Ile Thr Cys Ser Val Ser Ser Thr Ile Ser Ser Asn
20 25 30
His Leu His Trp Phe Gln Gln Lys Ser Asp Thr Ser Pro Lys Pro Trp
35 40 45
Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Val Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro
85 90 95
Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Arg Arg Ala Asp Ala
100 105 110
Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser
115 120 125
Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp
130 135 140
Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val
145 150 155 160
Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met
165 170 175
Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser
180 185 190
Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys
195 200 205
Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 126
<211> 648
<212> DNA
<213> Mus musculus
<400> 126
gaaattgtgc tcacccagtc tccagcactc atggctgcat ctccggggga gaaggtcacc 60
atcacctgca gtgtcagttc aactataagt tccaaccact tgcactggtt ccagcagaag 120
tcagacacct cccccaaacc ctggatttat ggcacatcca acctggcttc tggagtccct 180
gttcgcttca gtggcagtgg atctgggacc tcttattctc tcacaatcag cagcatggag 240
gctgaggatg ctgccactta ttactgtcaa cagtggagta gttacccact cacgttcggc 300
gctgggacca agctggagct gagacgggct gatgctgcac caactgtatc catcttccca 360
ccatccagtg agcagttaac atctggaggt gcctcagtcg tgtgcttctt gaacaacttc 420
taccccaaag acatcaatgt caagtggaag attgatggca gtgaacgaca aaatggcgtc 480
ctgaacagtt ggactgatca ggacagcaaa gacagcacct acagcatgag cagcaccctc 540
acgttgacca aggacgagta tgaacgacat aacagctata cctgtgaggc cactcacaag 600
acatcaactt cacccattgt caagagcttc aacaggaatg agtgttag 648
<210> 127
<211> 237
<212> PRT
<213> Mus musculus
<400> 127
Met Asp Phe His Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
Val Ile Leu Ser Ser Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Leu
20 25 30
Met Ala Ala Ser Pro Gly Glu Lys Val Thr Ile Thr Cys Ser Val Ser
35 40 45
Ser Thr Ile Ser Ser Asn His Leu His Trp Phe Gln Gln Lys Ser Asp
50 55 60
Thr Ser Pro Lys Pro Trp Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly
65 70 75 80
Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu
85 90 95
Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln
100 105 110
Gln Trp Ser Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu
115 120 125
Leu Arg Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 128
<211> 714
<212> DNA
<213> Mus musculus
<400> 128
atggattttc atgtgcagat tttcagcttc atgctaatca gtgtcacagt cattttgtcc 60
agtggagaaa ttgtgctcac ccagtctcca gcactcatgg ctgcatctcc gggggagaag 120
gtcaccatca cctgcagtgt cagttcaact ataagttcca accacttgca ctggttccag 180
cagaagtcag acacctcccc caaaccctgg atttatggca catccaacct ggcttctgga 240
gtccctgttc gcttcagtgg cagtggatct gggacctctt attctctcac aatcagcagc 300
atggaggctg aggatgctgc cacttattac tgtcaacagt ggagtagtta cccactcacg 360
ttcggcgctg ggaccaagct ggagctgaga cgggctgatg ctgcaccaac tgtatccatc 420
ttcccaccat ccagtgagca gttaacatct ggaggtgcct cagtcgtgtg cttcttgaac 480
aacttctacc ccaaagacat caatgtcaag tggaagattg atggcagtga acgacaaaat 540
ggcgtcctga acagttggac tgatcaggac agcaaagaca gcacctacag catgagcagc 600
accctcacgt tgaccaagga cgagtatgaa cgacataaca gctatacctg tgaggccact 660
cacaagacat caacttcacc cattgtcaag agcttcaaca ggaatgagtg ttag 714
<210> 129
<211> 449
<212> PRT
<213> Mus musculus
<400> 129
Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala
1 5 10 15
Leu Val Lys Leu Ser Cys Thr Ala Ser Asp Phe Asn Ile Lys Asp Phe
20 25 30
Tyr Leu His Trp Met Arg Gln Arg Pro Glu Gln Gly Leu Asp Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asn Gly Asp Thr Leu Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Lys Ala Thr Leu Thr Thr Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Ser Gly Leu Thr Ser Glu Thr Thr Ala Val Tyr Tyr Cys
85 90 95
Ser Arg Glu Ala Asp Tyr Phe His Asp Gly Thr Ser Tyr Trp Tyr Phe
100 105 110
Asp Val Trp Gly Ala Gly Thr Thr Ile Thr Val Ser Ser Ala Lys Thr
115 120 125
Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr
130 135 140
Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser
180 185 190
Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn
195 200 205
Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro
210 215 220
Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser
225 230 235 240
Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr
245 250 255
Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp
260 265 270
Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr
275 280 285
Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser
290 295 300
Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr
340 345 350
Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr
355 360 365
Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln
370 375 380
Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met
385 390 395 400
Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys
405 410 415
Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu
420 425 430
Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly
435 440 445
Lys
<210> 130
<211> 1350
<212> DNA
<213> Mus musculus
<400> 130
gaggttcagc tgcagcagtc tggggctgaa cttgtgaggc caggggcctt agtcaagttg 60
tcctgcacag cttctgactt caacattaaa gacttctatc tacactggat gaggcagcgg 120
cctgaacagg gcctggactg gattggaagg attgatcctg agaatggtga tactttatat 180
gacccgaagt tccaggacaa ggccactctt acaacagaca catcctccaa cacagcctac 240
ctgcagctca gcggcctgac atctgagacc actgccgtct attactgttc tagagaggcg 300
gattatttcc acgatggtac ctcctactgg tacttcgatg tctggggcgc agggaccaca 360
atcaccgtct cctcagccaa aacgacaccc ccatctgtct atccactggc ccctggatct 420
gctgcccaaa ctaactccat ggtgaccctg ggatgcctgg tcaagggcta tttccctgag 480
ccagtgacag tgacctggaa ctctggatcc ctgtccagcg gtgtgcacac cttcccagct 540
gtcctgcagt ctgacctcta cactctgagc agctcagtga ctgtcccctc cagcacctgg 600
cccagcgaga ccgtcacctg caacgttgcc cacccggcca gcagcaccaa ggtggacaag 660
aaaattgtgc ccagggattg tggttgtaag ccttgcatat gtacagtccc agaagtatca 720
tctgtcttca tcttcccccc aaagcccaag gatgtgctca ccattactct gactcctaag 780
gtcacgtgtg ttgtggtaga catcagcaag gatgatcccg aggtccagtt cagctggttt 840
gtagatgatg tggaggtgca cacagctcag acgcaacccc gggaggagca gttcaacagc 900
actttccgct cagtcagtga acttcccatc atgcaccagg actggctcaa tggcaaggag 960
ttcaaatgca gggtcaacag tgcagctttc cctgccccca tcgagaaaac catctccaaa 1020
accaaaggca gaccgaaggc tccacaggtg tacaccattc cacctcccaa ggagcagatg 1080
gccaaggata aagtcagtct gacctgcatg ataacagact tcttccctga agacattact 1140
gtggagtggc agtggaatgg gcagccagcg gagaactaca agaacactca gcccatcatg 1200
gacacagatg gctcttactt catctacagc aagctcaatg tgcagaagag caactgggag 1260
gcaggaaata ctttcacctg ctctgtgtta catgagggcc tgcacaacca ccatactgag 1320
aagagcctct cccactctcc tggtaaatga 1350
<210> 131
<211> 468
<212> PRT
<213> Mus musculus
<400> 131
Met Lys Cys Ser Trp Val Ile Phe Phe Leu Met Ala Val Val Thr Gly
1 5 10 15
Val Asn Ser Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg
20 25 30
Pro Gly Ala Leu Val Lys Leu Ser Cys Thr Ala Ser Asp Phe Asn Ile
35 40 45
Lys Asp Phe Tyr Leu His Trp Met Arg Gln Arg Pro Glu Gln Gly Leu
50 55 60
Asp Trp Ile Gly Arg Ile Asp Pro Glu Asn Gly Asp Thr Leu Tyr Asp
65 70 75 80
Pro Lys Phe Gln Asp Lys Ala Thr Leu Thr Thr Asp Thr Ser Ser Asn
85 90 95
Thr Ala Tyr Leu Gln Leu Ser Gly Leu Thr Ser Glu Thr Thr Ala Val
100 105 110
Tyr Tyr Cys Ser Arg Glu Ala Asp Tyr Phe His Asp Gly Thr Ser Tyr
115 120 125
Trp Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Ile Thr Val Ser Ser
130 135 140
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
145 150 155 160
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
165 170 175
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
180 185 190
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
195 200 205
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val
210 215 220
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
225 230 235 240
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
245 250 255
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
260 265 270
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
275 280 285
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
290 295 300
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
305 310 315 320
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
355 360 365
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
370 375 380
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
385 390 395 400
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
405 410 415
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn
420 425 430
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
435 440 445
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
450 455 460
Ser Pro Gly Lys
465
<210> 132
<211> 1407
<212> DNA
<213> Mus musculus
<400> 132
atgaaatgca gctgggtcat cttcttcctg atggcagtgg ttacaggggt caattcagag 60
gttcagctgc agcagtctgg ggctgaactt gtgaggccag gggccttagt caagttgtcc 120
tgcacagctt ctgacttcaa cattaaagac ttctatctac actggatgag gcagcggcct 180
gaacagggcc tggactggat tggaaggatt gatcctgaga atggtgatac tttatatgac 240
ccgaagttcc aggacaaggc cactcttaca acagacacat cctccaacac agcctacctg 300
cagctcagcg gcctgacatc tgagaccact gccgtctatt actgttctag agaggcggat 360
tatttccacg atggtacctc ctactggtac ttcgatgtct ggggcgcagg gaccacaatc 420
accgtctcct cagccaaaac gacaccccca tctgtctatc cactggcccc tggatctgct 480
gcccaaacta actccatggt gaccctggga tgcctggtca agggctattt ccctgagcca 540
gtgacagtga cctggaactc tggatccctg tccagcggtg tgcacacctt cccagctgtc 600
ctgcagtctg acctctacac tctgagcagc tcagtgactg tcccctccag cacctggccc 660
agcgagaccg tcacctgcaa cgttgcccac ccggccagca gcaccaaggt ggacaagaaa 720
attgtgccca gggattgtgg ttgtaagcct tgcatatgta cagtcccaga agtatcatct 780
gtcttcatct tccccccaaa gcccaaggat gtgctcacca ttactctgac tcctaaggtc 840
acgtgtgttg tggtagacat cagcaaggat gatcccgagg tccagttcag ctggtttgta 900
gatgatgtgg aggtgcacac agctcagacg caaccccggg aggagcagtt caacagcact 960
ttccgctcag tcagtgaact tcccatcatg caccaggact ggctcaatgg caaggagttc 1020
aaatgcaggg tcaacagtgc agctttccct gcccccatcg agaaaaccat ctccaaaacc 1080
aaaggcagac cgaaggctcc acaggtgtac accattccac ctcccaagga gcagatggcc 1140
aaggataaag tcagtctgac ctgcatgata acagacttct tccctgaaga cattactgtg 1200
gagtggcagt ggaatgggca gccagcggag aactacaaga acactcagcc catcatggac 1260
acagatggct cttacttcat ctacagcaag ctcaatgtgc agaagagcaa ctgggaggca 1320
ggaaatactt tcacctgctc tgtgttacat gagggcctgc acaaccacca tactgagaag 1380
agcctctccc actctcctgg taaatga 1407
<210> 133
<211> 214
<212> PRT
<213> Mus musculus
<400> 133
Asp Ile Gln Met Thr Gln Ile Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile
35 40 45
Phe Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr Asn Leu Glu Gln
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 134
<211> 645
<212> DNA
<213> Mus musculus
<400> 134
gatatccaga tgacacagat tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 60
atcagttgca gggcaagtca agacattagc aattatttaa actggtatca gcagaaacca 120
gatggaactt ttaaactcct tatcttctac acatcaagat tactctcagg agtcccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 240
gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 300
gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645
<210> 135
<211> 234
<212> PRT
<213> Mus musculus
<400> 135
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Ile Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe
50 55 60
Lys Leu Leu Ile Phe Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr
85 90 95
Asn Leu Glu Gln Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp
100 105 110
Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 136
<211> 705
<212> DNA
<213> Mus musculus
<400> 136
atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt 60
gatatccaga tgacacagat tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 120
atcagttgca gggcaagtca agacattagc aattatttaa actggtatca gcagaaacca 180
gatggaactt ttaaactcct tatcttctac acatcaagat tactctcagg agtcccatca 240
aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 300
gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 360
gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 705
<210> 137
<211> 447
<212> PRT
<213> Mus musculus
<400> 137
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Thr Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro
115 120 125
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
130 135 140
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
180 185 190
Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala
195 200 205
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
210 215 220
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
245 250 255
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
260 265 270
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
290 295 300
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
305 310 315 320
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
340 345 350
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
355 360 365
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
370 375 380
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
385 390 395 400
Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
405 410 415
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
420 425 430
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 138
<211> 1344
<212> DNA
<213> Mus musculus
<400> 138
gaggtccaac tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata tacattcact gactacaaca tgcactgggt gaagcagaac 120
caaggaaaga ccctagagtg gataggagaa attaatccta acagtggtgg tgctggctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccac cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300
tacgatgata tctacgacga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360
gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420
caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480
acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540
cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600
gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660
gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720
ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780
tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840
gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900
cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960
tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020
ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080
gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140
tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200
gatggctctt acttcatcta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260
aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320
ctctcccact ctcctggtaa atga 1344
<210> 139
<211> 466
<212> PRT
<213> Mus musculus
<400> 139
Met Gly Trp Ser Trp Thr Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Thr Leu
50 55 60
Glu Trp Ile Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys
130 135 140
Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln
145 150 155 160
Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser
195 200 205
Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys
210 215 220
Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val
225 230 235 240
Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val
245 250 255
Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile
260 265 270
Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp
275 280 285
Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His
290 295 300
Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr
355 360 365
Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu
370 375 380
Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp
385 390 395 400
Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile
405 410 415
Met Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln
420 425 430
Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His
435 440 445
Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro
450 455 460
Gly Lys
465
<210> 140
<211> 1401
<212> DNA
<213> Mus musculus
<400> 140
atgggatgga gctggacctt tctcttcctc ctgtcaggaa ctgcaggtgt cctctctgag 60
gtccaactgc aacagtctgg acctgaacta atgaagcctg gggcttcagt gaagatgtcc 120
tgcaaggctt ctggatatac attcactgac tacaacatgc actgggtgaa gcagaaccaa 180
ggaaagaccc tagagtggat aggagaaatt aatcctaaca gtggtggtgc tggctacaac 240
cagaagttca agggcaaggc cacattgact gtagacaagt cctccaccac agcctacatg 300
gagctccgca gcctgacatc tgaggactct gcagtctatt actgtgcaag attgggctac 360
gatgatatct acgacgactg gtacttcgat gtctggggcg cagggaccac ggtcaccgtc 420
tcctcagcca aaacgacacc cccatctgtc tatccactgg cccctggatc tgctgcccaa 480
actaactcca tggtgaccct gggatgcctg gtcaagggct atttccctga gccagtgaca 540
gtgacctgga actctggatc cctgtccagc ggtgtgcaca ccttcccagc tgtcctgcag 600
tctgacctct acactctgag cagctcagtg actgtcccct ccagcacctg gcccagcgag 660
accgtcacct gcaacgttgc ccacccggcc agcagcacca aggtggacaa gaaaattgtg 720
cccagggatt gtggttgtaa gccttgcata tgtacagtcc cagaagtatc atctgtcttc 780
atcttccccc caaagcccaa ggatgtgctc accattactc tgactcctaa ggtcacgtgt 840
gttgtggtag acatcagcaa ggatgatccc gaggtccagt tcagctggtt tgtagatgat 900
gtggaggtgc acacagctca gacgcaaccc cgggaggagc agttcaacag cactttccgc 960
tcagtcagtg aacttcccat catgcaccag gactggctca atggcaagga gttcaaatgc 1020
agggtcaaca gtgcagcttt ccctgccccc atcgagaaaa ccatctccaa aaccaaaggc 1080
agaccgaagg ctccacaggt gtacaccatt ccacctccca aggagcagat ggccaaggat 1140
aaagtcagtc tgacctgcat gataacagac ttcttccctg aagacattac tgtggagtgg 1200
cagtggaatg ggcagccagc ggagaactac aagaacactc agcccatcat ggacacagat 1260
ggctcttact tcatctacag caagctcaat gtgcagaaga gcaactggga ggcaggaaat 1320
actttcacct gctctgtgtt acatgagggc ctgcacaacc accatactga gaagagcctc 1380
tcccactctc ctggtaaatg a 1401
<210> 141
<211> 214
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 141
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 142
<211> 642
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 142
gacatccaga tgacccagtc tccatcctcc ctctccgcat ccgtaggcga ccgcgtaacc 60
ataacatgta gagcatctca agatatttcc aactatttga attggtacca acaaaaaccc 120
ggcaaagcac ctaaactcct catttactat acatcaagac tcctctccgg cgttccatca 180
cgattctcag gctccggctc cggcacagat ttcacactca ctatttcctc cctccaacca 240
gaagattttg caacctatta ctgtcaacaa ggcgatacac tcccatacac attcggcggc 300
ggcacaaaag ttgaaattaa acgtacggtg gctgcaccat ctgtcttcat cttcccgcca 360
tctgatgagc agttgaaatc tggaactgcc tctgttgtgt gcctgctgaa taacttctat 420
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 480
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg 540
ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 600
ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 642
<210> 143
<211> 236
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 143
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu Leu Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Gly Asp Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp
130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
145 150 155 160
Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190
Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205
Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
210 215 220
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 144
<211> 708
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 144
atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60
agatgtgaca tccagatgac ccagtctcca tcctccctct ccgcatccgt aggcgaccgc 120
gtaaccataa catgtagagc atctcaagat atttccaact atttgaattg gtaccaacaa 180
aaacccggca aagcacctaa actcctcatt tactatacat caagactcct ctccggcgtt 240
ccatcacgat tctcaggctc cggctccggc acagatttca cactcactat ttcctccctc 300
caaccagaag attttgcaac ctattactgt caacaaggcg atacactccc atacacattc 360
ggcggcggca caaaagttga aattaaacgt acggtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc 600
ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> 145
<211> 449
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 145
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
210 215 220
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
290 295 300
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
Lys
<210> 146
<211> 1347
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 146
gaggtgcagc tggtgcagag cggcgccgag gtaaaaaaac caggagcaag cgttaaagtt 60
tcttgtaaag caagcggata tacatttaca gattacaaca tgcattgggt aagacaagcg 120
ccaggacaag gattggaatg gatgggcgaa attaacccta atagtggagg agcaggctac 180
aatcaaaaat tcaaagggag agttacaatg acaacagaca caagcacttc aacagcatat 240
atggaactgc gatcacttag aagcgacgat acagctgtat actattgcgc acgacttggg 300
tatgatgata tatatgatga ctggtatttc gatgtttggg gccagggaac aacagttacc 360
gtctctagtg cctccaccaa gggcccatcg gtcttccccc tggcgccctg ctccaggagc 420
acctccgaga gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 480
acggtgtcgt ggaactcagg cgctctgacc agcggcgtgc acaccttccc agctgtccta 540
cagtcctcag gactctactc cctcagcagc gtggtgaccg tgccctccag caacttcggc 600
acccagacct acacctgcaa cgtagatcac aagcccagca acaccaaggt ggacaagaca 660
gttgagcgca aatgttgtgt cgagtgccca ccgtgcccag caccacctgt ggcaggaccg 720
tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 780
gtcacgtgcg tggtggtgga cgtgagccac gaagaccccg aggtccagtt caactggtac 840
gtggacggcg tggaggtgca taatgccaag acaaagccac gggaggagca gttcaacagc 900
acgttccgtg tggtcagcgt cctcaccgtt gtgcaccagg actggctgaa cggcaaggag 960
tacaagtgca aggtctccaa caaaggcctc ccagccccca tcgagaaaac catctccaaa 1020
accaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1080
accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1140
gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacacc tcccatgctg 1200
gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1260
caggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1320
aagagcctct ccctgtctcc gggtaaa 1347
<210> 147
<211> 468
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 147
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser
130 135 140
Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr
145 150 155 160
Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
195 200 205
Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr
210 215 220
Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val
225 230 235 240
Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val
245 250 255
Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
260 265 270
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
275 280 285
His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
290 295 300
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
305 310 315 320
Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn
325 330 335
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro
340 345 350
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln
355 360 365
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
370 375 380
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
385 390 395 400
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
405 410 415
Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
420 425 430
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
435 440 445
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
450 455 460
Ser Pro Gly Lys
465
<210> 148
<211> 1404
<212> DNA
<213> Mus musculus
<400> 148
atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactccgag 60
gtgcagctgg tgcagagcgg cgccgaggta aaaaaaccag gagcaagcgt taaagtttct 120
tgtaaagcaa gcggatatac atttacagat tacaacatgc attgggtaag acaagcgcca 180
ggacaaggat tggaatggat gggcgaaatt aaccctaata gtggaggagc aggctacaat 240
caaaaattca aagggagagt tacaatgaca acagacacaa gcacttcaac agcatatatg 300
gaactgcgat cacttagaag cgacgataca gctgtatact attgcgcacg acttgggtat 360
gatgatatat atgatgactg gtatttcgat gtttggggcc agggaacaac agttaccgtc 420
tctagtgcct ccaccaaggg cccatcggtc ttccccctgg cgccctgctc caggagcacc 480
tccgagagca cagcggccct gggctgcctg gtcaaggact acttccccga accggtgacg 540
gtgtcgtgga actcaggcgc tctgaccagc ggcgtgcaca ccttcccagc tgtcctacag 600
tcctcaggac tctactccct cagcagcgtg gtgaccgtgc cctccagcaa cttcggcacc 660
cagacctaca cctgcaacgt agatcacaag cccagcaaca ccaaggtgga caagacagtt 720
gagcgcaaat gttgtgtcga gtgcccaccg tgcccagcac cacctgtggc aggaccgtca 780
gtcttcctct tccccccaaa acccaaggac accctcatga tctcccggac ccctgaggtc 840
acgtgcgtgg tggtggacgt gagccacgaa gaccccgagg tccagttcaa ctggtacgtg 900
gacggcgtgg aggtgcataa tgccaagaca aagccacggg aggagcagtt caacagcacg 960
ttccgtgtgg tcagcgtcct caccgttgtg caccaggact ggctgaacgg caaggagtac 1020
aagtgcaagg tctccaacaa aggcctccca gcccccatcg agaaaaccat ctccaaaacc 1080
aaagggcagc cccgagaacc acaggtgtac accctgcccc catcccggga ggagatgacc 1140
aagaaccagg tcagcctgac ctgcctggtc aaaggcttct accccagcga catcgccgtg 1200
gagtgggaga gcaatgggca gccggagaac aactacaaga ccacacctcc catgctggac 1260
tccgacggct ccttcttcct ctacagcaag ctcaccgtgg acaagagcag gtggcagcag 1320
gggaacgtct tctcatgctc cgtgatgcat gaggctctgc acaaccacta cacgcagaag 1380
agcctctccc tgtctccggg taaa 1404
<210> 149
<211> 214
<212> PRT
<213> Mus musculus
<400> 149
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Phe Gln Gln Lys Pro Asp Gly Thr Leu Lys Leu Leu Ile
35 40 45
Phe Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 150
<211> 645
<212> DNA
<213> Mus musculus
<400> 150
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60
atcagttgca gggcaagtca ggacattagc aattatttaa actggtttca gcagaaacca 120
gatggaactc ttaaactcct gatcttctac acatcaagat tacactcagg agttccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggagcaa 240
gaagatattg ccacttactt ttgccaacag ggtgatacgc ttccgtacac gttcgggggg 300
gggaccaagc tggaaataag acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645
<210> 151
<211> 234
<212> PRT
<213> Mus musculus
<400> 151
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Phe Gln Gln Lys Pro Asp Gly Thr Leu
50 55 60
Lys Leu Leu Ile Phe Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser
85 90 95
Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asp
100 105 110
Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Arg Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 152
<211> 705
<212> DNA
<213> Mus musculus
<400> 152
atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt 60
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 120
atcagttgca gggcaagtca ggacattagc aattatttaa actggtttca gcagaaacca 180
gatggaactc ttaaactcct gatcttctac acatcaagat tacactcagg agttccatca 240
aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggagcaa 300
gaagatattg ccacttactt ttgccaacag ggtgatacgc ttccgtacac gttcgggggg 360
gggaccaagc tggaaataag acgggctgat gctgcaccaa ctgtatccat cttcccacca 420
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 705
<210> 153
<211> 447
<212> PRT
<213> Mus musculus
<400> 153
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ser Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Val Tyr Asp Gly Ser Tyr Glu Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro
115 120 125
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
130 135 140
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
180 185 190
Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala
195 200 205
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
210 215 220
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
245 250 255
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
260 265 270
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
290 295 300
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
305 310 315 320
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
340 345 350
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
355 360 365
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
370 375 380
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
385 390 395 400
Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
405 410 415
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
420 425 430
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 154
<211> 1344
<212> DNA
<213> Mus musculus
<400> 154
gaggtccagc tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact gactacaaca tgcactgggt gaaacagaac 120
caaggaaaga gcctagagtg gataggagaa attaatccta acagtggtgg tagtggctac 180
aaccaaaagt tcaaaggcaa ggccacattg actgtagaca agtcttccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattggtc 300
tacgatggca gctacgagga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360
gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420
caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480
acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540
cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600
gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660
gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720
ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780
tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840
gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900
cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960
tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020
ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080
gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140
tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200
gatggctctt acttcatcta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260
aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320
ctctcccact ctcctggtaa atga 1344
<210> 155
<211> 466
<212> PRT
<213> Mus musculus
<400> 155
Met Gly Trp Ser Trp Thr Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Ser Leu
50 55 60
Glu Trp Ile Gly Glu Ile Asn Pro Asn Ser Gly Gly Ser Gly Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Leu Val Tyr Asp Gly Ser Tyr Glu Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys
130 135 140
Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln
145 150 155 160
Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser
195 200 205
Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys
210 215 220
Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val
225 230 235 240
Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val
245 250 255
Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile
260 265 270
Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp
275 280 285
Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His
290 295 300
Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr
355 360 365
Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu
370 375 380
Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp
385 390 395 400
Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile
405 410 415
Met Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln
420 425 430
Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His
435 440 445
Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro
450 455 460
Gly Lys
465
<210> 156
<211> 1401
<212> DNA
<213> Mus musculus
<400> 156
atgggatgga gctggacctt tctcttcctc ctgtcaggaa ctgcaggtgt cctctctgag 60
gtccagctgc aacagtctgg acctgaacta atgaagcctg gggcttcagt gaagatgtcc 120
tgcaaggctt ctggatacac attcactgac tacaacatgc actgggtgaa acagaaccaa 180
ggaaagagcc tagagtggat aggagaaatt aatcctaaca gtggtggtag tggctacaac 240
caaaagttca aaggcaaggc cacattgact gtagacaagt cttccagcac agcctacatg 300
gagctccgca gcctgacatc tgaggactct gcagtctatt actgtgcaag attggtctac 360
gatggcagct acgaggactg gtacttcgat gtctggggcg cagggaccac ggtcaccgtc 420
tcctcagcca aaacgacacc cccatctgtc tatccactgg cccctggatc tgctgcccaa 480
actaactcca tggtgaccct gggatgcctg gtcaagggct atttccctga gccagtgaca 540
gtgacctgga actctggatc cctgtccagc ggtgtgcaca ccttcccagc tgtcctgcag 600
tctgacctct acactctgag cagctcagtg actgtcccct ccagcacctg gcccagcgag 660
accgtcacct gcaacgttgc ccacccggcc agcagcacca aggtggacaa gaaaattgtg 720
cccagggatt gtggttgtaa gccttgcata tgtacagtcc cagaagtatc atctgtcttc 780
atcttccccc caaagcccaa ggatgtgctc accattactc tgactcctaa ggtcacgtgt 840
gttgtggtag acatcagcaa ggatgatccc gaggtccagt tcagctggtt tgtagatgat 900
gtggaggtgc acacagctca gacgcaaccc cgggaggagc agttcaacag cactttccgc 960
tcagtcagtg aacttcccat catgcaccag gactggctca atggcaagga gttcaaatgc 1020
agggtcaaca gtgcagcttt ccctgccccc atcgagaaaa ccatctccaa aaccaaaggc 1080
agaccgaagg ctccacaggt gtacaccatt ccacctccca aggagcagat ggccaaggat 1140
aaagtcagtc tgacctgcat gataacagac ttcttccctg aagacattac tgtggagtgg 1200
cagtggaatg ggcagccagc ggagaactac aagaacactc agcccatcat ggacacagat 1260
ggctcttact tcatctacag caagctcaat gtgcagaaga gcaactggga ggcaggaaat 1320
actttcacct gctctgtgtt acatgagggc ctgcacaacc accatactga gaagagcctc 1380
tcccactctc ctggtaaatg a 1401
<210> 157
<211> 214
<212> PRT
<213> Mus musculus
<400> 157
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Cys Cys Arg Ala Ser Gln Val Ile Thr Asn Tyr
20 25 30
Leu Tyr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 158
<211> 642
<212> DNA
<213> Mus musculus
<400> 158
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 60
atctgttgca gggcaagtca ggtcattacc aattatttat actggtatca gcagaaacca 120
gatggaactt ttaaactcct gatctactac acatcaagat tacactcagg agtcccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggaacag 240
gaagatattg ccacttactt ttgccaacag ggtgatacgc ttccgtacac gttcggaggg 300
gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gt 642
<210> 159
<211> 234
<212> PRT
<213> Mus musculus
<400> 159
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Thr Ile Cys Cys Arg Ala Ser Gln Val
35 40 45
Ile Thr Asn Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe
50 55 60
Lys Leu Leu Ile Tyr Tyr Thr Ser Arg Leu His Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser
85 90 95
Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asp
100 105 110
Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 160
<211> 702
<212> DNA
<213> Mus musculus
<400> 160
atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt 60
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcacc 120
atctgttgca gggcaagtca ggtcattacc aattatttat actggtatca gcagaaacca 180
gatggaactt ttaaactcct gatctactac acatcaagat tacactcagg agtcccatca 240
aggttcagtg gcagtgggtc tggaacagat tattctctca ccattagcaa cctggaacag 300
gaagatattg ccacttactt ttgccaacag ggtgatacgc ttccgtacac gttcggaggg 360
gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gt 702
<210> 161
<211> 447
<212> PRT
<213> Mus musculus
<400> 161
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Met Lys Gln Asn Gln Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Gln Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Arg Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Tyr Val Gly Asn Tyr Glu Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro
115 120 125
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
130 135 140
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
180 185 190
Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala
195 200 205
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
210 215 220
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
245 250 255
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
260 265 270
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
290 295 300
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
305 310 315 320
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
340 345 350
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
355 360 365
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
370 375 380
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
385 390 395 400
Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
405 410 415
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
420 425 430
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 162
<211> 1341
<212> DNA
<213> Mus musculus
<400> 162
gaggtccagc tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact gactacaaca tgcactggat gaagcagaac 120
caaggaaaga gcctagaatg gataggagaa attaatccta acagtggtgg tgctggctac 180
aaccagcagt tcaaaggcaa ggccacattg actgtagaca agtcctccag gacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300
tacgttggta attacgagga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360
gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420
caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480
acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540
cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600
gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660
gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720
ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780
tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840
gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900
cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960
tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020
ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080
gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140
tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200
gatggctctt acttcatcta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260
aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320
ctctcccact ctcctggtaa a 1341
<210> 163
<211> 466
<212> PRT
<213> Mus musculus
<400> 163
Met Gly Trp Ser Trp Thr Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Met Lys Gln Asn Gln Gly Lys Ser Leu
50 55 60
Glu Trp Ile Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn
65 70 75 80
Gln Gln Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Arg
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Leu Gly Tyr Val Gly Asn Tyr Glu Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys
130 135 140
Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln
145 150 155 160
Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser
195 200 205
Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys
210 215 220
Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val
225 230 235 240
Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val
245 250 255
Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile
260 265 270
Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp
275 280 285
Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His
290 295 300
Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr
355 360 365
Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu
370 375 380
Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp
385 390 395 400
Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile
405 410 415
Met Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln
420 425 430
Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His
435 440 445
Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro
450 455 460
Gly Lys
465
<210> 164
<211> 1398
<212> DNA
<213> Mus musculus
<400> 164
atgggatgga gctggacctt tctcttcctc ctgtcaggaa ctgcaggtgt cctctctgag 60
gtccagctgc aacagtctgg acctgaacta atgaagcctg gggcttcagt gaagatgtcc 120
tgcaaggctt ctggatacac attcactgac tacaacatgc actggatgaa gcagaaccaa 180
ggaaagagcc tagaatggat aggagaaatt aatcctaaca gtggtggtgc tggctacaac 240
cagcagttca aaggcaaggc cacattgact gtagacaagt cctccaggac agcctacatg 300
gagctccgca gcctgacatc tgaggactct gcagtctatt actgtgcaag attgggctac 360
gttggtaatt acgaggactg gtacttcgat gtctggggcg cagggaccac ggtcaccgtc 420
tcctcagcca aaacgacacc cccatctgtc tatccactgg cccctggatc tgctgcccaa 480
actaactcca tggtgaccct gggatgcctg gtcaagggct atttccctga gccagtgaca 540
gtgacctgga actctggatc cctgtccagc ggtgtgcaca ccttcccagc tgtcctgcag 600
tctgacctct acactctgag cagctcagtg actgtcccct ccagcacctg gcccagcgag 660
accgtcacct gcaacgttgc ccacccggcc agcagcacca aggtggacaa gaaaattgtg 720
cccagggatt gtggttgtaa gccttgcata tgtacagtcc cagaagtatc atctgtcttc 780
atcttccccc caaagcccaa ggatgtgctc accattactc tgactcctaa ggtcacgtgt 840
gttgtggtag acatcagcaa ggatgatccc gaggtccagt tcagctggtt tgtagatgat 900
gtggaggtgc acacagctca gacgcaaccc cgggaggagc agttcaacag cactttccgc 960
tcagtcagtg aacttcccat catgcaccag gactggctca atggcaagga gttcaaatgc 1020
agggtcaaca gtgcagcttt ccctgccccc atcgagaaaa ccatctccaa aaccaaaggc 1080
agaccgaagg ctccacaggt gtacaccatt ccacctccca aggagcagat ggccaaggat 1140
aaagtcagtc tgacctgcat gataacagac ttcttccctg aagacattac tgtggagtgg 1200
cagtggaatg ggcagccagc ggagaactac aagaacactc agcccatcat ggacacagat 1260
ggctcttact tcatctacag caagctcaat gtgcagaaga gcaactggga ggcaggaaat 1320
actttcacct gctctgtgtt acatgagggc ctgcacaacc accatactga gaagagcctc 1380
tcccactctc ctggtaaa 1398
<210> 165
<211> 214
<212> PRT
<213> Mus musculus
<400> 165
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile
35 40 45
Phe Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr Asn Leu Glu Gln
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 166
<211> 645
<212> DNA
<213> Mus musculus
<400> 166
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 60
atcagttgca gggcaagtca agacattagc aattatttaa actggtatca gcagaaacca 120
gatggaactt ttaaactcct tatcttctac acatcaagat tactctcagg agtcccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 240
gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 300
gggaccaaac tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645
<210> 167
<211> 234
<212> PRT
<213> Mus musculus
<400> 167
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe
50 55 60
Lys Leu Leu Ile Phe Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr
85 90 95
Asn Leu Glu Gln Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp
100 105 110
Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 168
<211> 705
<212> DNA
<213> Mus musculus
<400> 168
atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt 60
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 120
atcagttgca gggcaagtca agacattagc aattatttaa actggtatca gcagaaacca 180
gatggaactt ttaaactcct tatcttctac acatcaagat tactctcagg agtcccatca 240
aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 300
gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 360
gggaccaaac tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 705
<210> 169
<211> 447
<212> PRT
<213> Mus musculus
<400> 169
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Thr Leu Asp Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro
115 120 125
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
130 135 140
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
180 185 190
Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala
195 200 205
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
210 215 220
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
245 250 255
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
260 265 270
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
290 295 300
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
305 310 315 320
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
340 345 350
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
355 360 365
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
370 375 380
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
385 390 395 400
Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
405 410 415
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
420 425 430
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 170
<211> 1344
<212> DNA
<213> Mus musculus
<400> 170
gaggtccaac tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata tacattcact gactacaaca tgcactgggt gaagcagaac 120
caaggaaaga ccctagactg gataggagaa attaatccta acagtggtgg tgctggctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccac cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300
tacgatgata tctacgacga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360
gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420
caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480
acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540
cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600
gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660
gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720
ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780
tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840
gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900
cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960
tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020
ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080
gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140
tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200
gatggctctt acttcatcta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260
aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320
ctctcccact ctcctggtaa atga 1344
<210> 171
<211> 466
<212> PRT
<213> Mus musculus
<400> 171
Met Gly Trp Ser Trp Thr Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Thr Leu
50 55 60
Asp Trp Ile Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys
130 135 140
Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln
145 150 155 160
Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser
195 200 205
Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys
210 215 220
Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val
225 230 235 240
Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val
245 250 255
Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile
260 265 270
Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp
275 280 285
Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His
290 295 300
Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr
355 360 365
Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu
370 375 380
Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp
385 390 395 400
Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile
405 410 415
Met Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln
420 425 430
Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His
435 440 445
Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro
450 455 460
Gly Lys
465
<210> 172
<211> 1401
<212> DNA
<213> Mus musculus
<400> 172
atgggatgga gctggacctt tctcttcctc ctgtcaggaa ctgcaggtgt cctctctgag 60
gtccaactgc aacagtctgg acctgaacta atgaagcctg gggcttcagt gaagatgtcc 120
tgcaaggctt ctggatatac attcactgac tacaacatgc actgggtgaa gcagaaccaa 180
ggaaagaccc tagactggat aggagaaatt aatcctaaca gtggtggtgc tggctacaac 240
cagaagttca agggcaaggc cacattgact gtagacaagt cctccaccac agcctacatg 300
gagctccgca gcctgacatc tgaggactct gcagtctatt actgtgcaag attgggctac 360
gatgatatct acgacgactg gtacttcgat gtctggggcg cagggaccac ggtcaccgtc 420
tcctcagcca aaacgacacc cccatctgtc tatccactgg cccctggatc tgctgcccaa 480
actaactcca tggtgaccct gggatgcctg gtcaagggct atttccctga gccagtgaca 540
gtgacctgga actctggatc cctgtccagc ggtgtgcaca ccttcccagc tgtcctgcag 600
tctgacctct acactctgag cagctcagtg actgtcccct ccagcacctg gcccagcgag 660
accgtcacct gcaacgttgc ccacccggcc agcagcacca aggtggacaa gaaaattgtg 720
cccagggatt gtggttgtaa gccttgcata tgtacagtcc cagaagtatc atctgtcttc 780
atcttccccc caaagcccaa ggatgtgctc accattactc tgactcctaa ggtcacgtgt 840
gttgtggtag acatcagcaa ggatgatccc gaggtccagt tcagctggtt tgtagatgat 900
gtggaggtgc acacagctca gacgcaaccc cgggaggagc agttcaacag cactttccgc 960
tcagtcagtg aacttcccat catgcaccag gactggctca atggcaagga gttcaaatgc 1020
agggtcaaca gtgcagcttt ccctgccccc atcgagaaaa ccatctccaa aaccaaaggc 1080
agaccgaagg ctccacaggt gtacaccatt ccacctccca aggagcagat ggccaaggat 1140
aaagtcagtc tgacctgcat gataacagac ttcttccctg aagacattac tgtggagtgg 1200
cagtggaatg ggcagccagc ggagaactac aagaacactc agcccatcat ggacacagat 1260
ggctcttact tcatctacag caagctcaat gtgcagaaga gcaactggga ggcaggaaat 1320
actttcacct gctctgtgtt acatgagggc ctgcacaacc accatactga gaagagcctc 1380
tcccactctc ctggtaaatg a 1401
<210> 173
<211> 214
<212> PRT
<213> Mus musculus
<400> 173
Asp Ile Gln Met Thr Gln Ile Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile
35 40 45
Phe Tyr Thr Ser Arg Leu Phe Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr Asn Leu Glu Gln
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 174
<211> 642
<212> DNA
<213> Mus musculus
<400> 174
gatatccaga tgacacagat tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 60
atcagttgca gggcaagtca agacattagc aattatttaa attggtatca gcagaaacca 120
gatggaactt ttaaactcct tatcttctac acatcaagat tattttcagg agtcccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 240
gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 300
gggaccaagg tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gt 642
<210> 175
<211> 234
<212> PRT
<213> Mus musculus
<400> 175
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Ile Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe
50 55 60
Lys Leu Leu Ile Phe Tyr Thr Ser Arg Leu Phe Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr
85 90 95
Asn Leu Glu Gln Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp
100 105 110
Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 176
<211> 702
<212> DNA
<213> Mus musculus
<400> 176
atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt 60
gatatccaga tgacacagat tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 120
atcagttgca gggcaagtca agacattagc aattatttaa attggtatca gcagaaacca 180
gatggaactt ttaaactcct tatcttctac acatcaagat tattttcagg agtcccatca 240
aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 300
gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 360
gggaccaagg tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gt 702
<210> 177
<211> 450
<212> PRT
<213> Mus musculus
<400> 177
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Thr
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Lys Gln Thr Gln Gly Lys Thr Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Lys Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Ala
115 120 125
Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser
130 135 140
Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Asp Val His Thr Phe
165 170 175
Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Leu Ser Ser Ser Val Thr
180 185 190
Val Thr Thr Trp Pro Ser Gln Thr Ile Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Ser Pro
210 215 220
Thr His Lys Pro Cys Pro Pro Cys Pro Ala Pro Asn Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile
245 250 255
Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val Ser Glu Asp
260 265 270
Asp Pro Asp Val His Val Ser Trp Phe Val Asn Asn Val Glu Val His
275 280 285
Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Ile Arg
290 295 300
Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys
305 310 315 320
Glu Phe Lys Cys Lys Val Asn Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Arg Thr Ile Ser Lys Pro Lys Gly Pro Val Arg Ala Pro Gln Val Tyr
340 345 350
Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu
355 360 365
Thr Cys Met Ile Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp
370 375 380
Thr Asn Asn Gly Gln Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu
405 410 415
Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His
420 425 430
Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr Pro
435 440 445
Gly Lys
450
<210> 178
<211> 1350
<212> DNA
<213> Mus musculus
<400> 178
gaggtccaac tgcaacagtc tggacctgaa ctaatgaagc ctgggacttc agtgaagatg 60
tcctgcaagg cttctggata tacattcact gactacaaca tgcactgggt gaagcagacc 120
caaggaaaga ccctagagtg gataggagaa attaatccta acagtggtgg tgctggctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccac cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aaaattgggc 300
tacgatgata tctacgacga ctggtatttc gatgtctggg gcgcagggac cacggtcacc 360
gtctcctcag ccaaaacaac agccccatcg gtctatccac tggcccctgt gtgtggagat 420
acaactggct cctcggtgac tctaggatgc ctggtcaagg gttatttccc tgagccagtg 480
accttgacct ggaactctgg atccctgtcc agtgatgtgc acaccttccc agctctcctg 540
cagtctggcc tctacaccct cagcagctca gtgactgtaa ccacctggcc cagccagacc 600
atcacctgca atgtggccca cccggcaagc agcaccaaag tggacaagaa aattgagccc 660
agagggtccc caacacataa accctgtcct ccatgcccag ctcctaacct cttgggtgga 720
ccatccgtct tcatcttccc tccaaagatc aaggatgtac tcatgatctc cctgagcccc 780
atggtcacgt gtgtggtggt ggatgtgagc gaggatgacc cagatgtcca tgtcagctgg 840
ttcgtgaaca acgtggaagt acacacagct cagacacaaa cccatagaga ggattacaac 900
agtactatcc gggtggtcag tgccctcccc atccagcacc aggactggat gagtggcaag 960
gagttcaaat gcaaggtcaa caacaaagcc ctcccagcgc ccatcgagag aaccatctca 1020
aaacccaaag ggccagtaag agctccacag gtatatgtct tgcctccacc agaagaagag 1080
atgactaaga aacaggtcac tctgacctgc atgatcacag acttcatgcc tgaagacatt 1140
tacgtggagt ggaccaacaa cgggcaaaca gagctaaact acaagaacac tgaaccagtc 1200
ctggactctg atggttctta cttcatgtac agcaagctga gagtggaaaa gaagaactgg 1260
gtggaaagaa atagctactc ctgttcagtg gtccacgagg gtctgcacaa tcaccacacg 1320
actaagagct tctcccggac tccgggtaaa 1350
<210> 179
<211> 469
<212> PRT
<213> Mus musculus
<400> 179
Met Gly Trp Ser Trp Thr Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys
20 25 30
Pro Gly Thr Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Val Lys Gln Thr Gln Gly Lys Thr Leu
50 55 60
Glu Trp Ile Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Lys Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys
130 135 140
Thr Thr Ala Pro Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr
145 150 155 160
Thr Gly Ser Ser Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
165 170 175
Glu Pro Val Thr Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Asp Val
180 185 190
His Thr Phe Pro Ala Leu Leu Gln Ser Gly Leu Tyr Thr Leu Ser Ser
195 200 205
Ser Val Thr Val Thr Thr Trp Pro Ser Gln Thr Ile Thr Cys Asn Val
210 215 220
Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg
225 230 235 240
Gly Ser Pro Thr His Lys Pro Cys Pro Pro Cys Pro Ala Pro Asn Leu
245 250 255
Leu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val
260 265 270
Leu Met Ile Ser Leu Ser Pro Met Val Thr Cys Val Val Val Asp Val
275 280 285
Ser Glu Asp Asp Pro Asp Val His Val Ser Trp Phe Val Asn Asn Val
290 295 300
Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser
305 310 315 320
Thr Ile Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met
325 330 335
Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Ala Leu Pro Ala
340 345 350
Pro Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Pro Val Arg Ala Pro
355 360 365
Gln Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln
370 375 380
Val Thr Leu Thr Cys Met Ile Thr Asp Phe Met Pro Glu Asp Ile Tyr
385 390 395 400
Val Glu Trp Thr Asn Asn Gly Gln Thr Glu Leu Asn Tyr Lys Asn Thr
405 410 415
Glu Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu
420 425 430
Arg Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser
435 440 445
Val Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser
450 455 460
Arg Thr Pro Gly Lys
465
<210> 180
<211> 1407
<212> DNA
<213> Mus musculus
<400> 180
atgggatgga gctggacctt tctcttcctc ctgtcaggaa ctgcaggtgt cctctctgag 60
gtccaactgc aacagtctgg acctgaacta atgaagcctg ggacttcagt gaagatgtcc 120
tgcaaggctt ctggatatac attcactgac tacaacatgc actgggtgaa gcagacccaa 180
ggaaagaccc tagagtggat aggagaaatt aatcctaaca gtggtggtgc tggctacaac 240
cagaagttca agggcaaggc cacattgact gtagacaagt cctccaccac agcctacatg 300
gagctccgca gcctgacatc tgaggactct gcagtctatt actgtgcaaa attgggctac 360
gatgatatct acgacgactg gtatttcgat gtctggggcg cagggaccac ggtcaccgtc 420
tcctcagcca aaacaacagc cccatcggtc tatccactgg cccctgtgtg tggagataca 480
actggctcct cggtgactct aggatgcctg gtcaagggtt atttccctga gccagtgacc 540
ttgacctgga actctggatc cctgtccagt gatgtgcaca ccttcccagc tctcctgcag 600
tctggcctct acaccctcag cagctcagtg actgtaacca cctggcccag ccagaccatc 660
acctgcaatg tggcccaccc ggcaagcagc accaaagtgg acaagaaaat tgagcccaga 720
gggtccccaa cacataaacc ctgtcctcca tgcccagctc ctaacctctt gggtggacca 780
tccgtcttca tcttccctcc aaagatcaag gatgtactca tgatctccct gagccccatg 840
gtcacgtgtg tggtggtgga tgtgagcgag gatgacccag atgtccatgt cagctggttc 900
gtgaacaacg tggaagtaca cacagctcag acacaaaccc atagagagga ttacaacagt 960
actatccggg tggtcagtgc cctccccatc cagcaccagg actggatgag tggcaaggag 1020
ttcaaatgca aggtcaacaa caaagccctc ccagcgccca tcgagagaac catctcaaaa 1080
cccaaagggc cagtaagagc tccacaggta tatgtcttgc ctccaccaga agaagagatg 1140
actaagaaac aggtcactct gacctgcatg atcacagact tcatgcctga agacatttac 1200
gtggagtgga ccaacaacgg gcaaacagag ctaaactaca agaacactga accagtcctg 1260
gactctgatg gttcttactt catgtacagc aagctgagag tggaaaagaa gaactgggtg 1320
gaaagaaata gctactcctg ttcagtggtc cacgagggtc tgcacaatca ccacacgact 1380
aagagcttct cccggactcc gggtaaa 1407
<210> 181
<211> 214
<212> PRT
<213> Mus musculus
<400> 181
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile
35 40 45
Phe Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr Asn Leu Glu Gln
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Leu Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 182
<211> 645
<212> DNA
<213> Mus musculus
<400> 182
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 60
atcagttgca gggcaagtca agacattagc aattatttaa actggtatca gcagaaacca 120
gatggaactt ttaaactcct tatcttctac acatcaagat tactctcagg agtcccatca 180
aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 240
gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 300
gggaccaaac tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacta 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645
<210> 183
<211> 234
<212> PRT
<213> Mus musculus
<400> 183
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe
50 55 60
Lys Leu Leu Ile Phe Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr
85 90 95
Asn Leu Glu Gln Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp
100 105 110
Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Leu Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 184
<211> 705
<212> DNA
<213> Mus musculus
<400> 184
atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt 60
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagggtctcc 120
atcagttgca gggcaagtca agacattagc aattatttaa actggtatca gcagaaacca 180
gatggaactt ttaaactcct tatcttctac acatcaagat tactctcagg agtcccatca 240
aggttcagtg gcagtgggtc tggaacagat tattctctca ccatttacaa cctggagcaa 300
gaagattttg ccacttactt ttgccaacag ggagatacgc ttccgtacac tttcggaggg 360
gggaccaaac tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacta 420
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 705
<210> 185
<211> 447
<212> PRT
<213> Mus musculus
<400> 185
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Thr Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro
115 120 125
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
130 135 140
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
180 185 190
Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala
195 200 205
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
210 215 220
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
245 250 255
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
260 265 270
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
290 295 300
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
305 310 315 320
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
340 345 350
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
355 360 365
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
370 375 380
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
385 390 395 400
Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
405 410 415
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
420 425 430
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 186
<211> 1344
<212> DNA
<213> Mus musculus
<400> 186
gaggtccaac tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata tacattcact gactacaaca tgcactgggt gaagcagaac 120
caaggaaaga ccctagaatg gataggagaa attaatccta acagtggtgg tgctggctac 180
aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccac cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300
tacgatgata tctacgacga ctggtacttc gatgtctggg gcgcagggac cacggtcacc 360
gtctcctcag ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420
caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480
acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540
cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600
gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660
gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720
ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780
tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840
gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900
cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960
tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020
ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080
gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140
tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200
gatggctctt acttcatcta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260
aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320
ctctcccact ctcctggtaa atga 1344
<210> 187
<211> 466
<212> PRT
<213> Mus musculus
<400> 187
Met Gly Trp Ser Trp Thr Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Val Lys Gln Asn Gln Gly Lys Thr Leu
50 55 60
Glu Trp Ile Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Thr
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys
130 135 140
Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln
145 150 155 160
Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser
195 200 205
Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys
210 215 220
Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val
225 230 235 240
Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val
245 250 255
Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile
260 265 270
Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp
275 280 285
Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His
290 295 300
Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr
355 360 365
Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu
370 375 380
Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp
385 390 395 400
Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile
405 410 415
Met Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln
420 425 430
Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His
435 440 445
Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro
450 455 460
Gly Lys
465
<210> 188
<211> 1401
<212> DNA
<213> Mus musculus
<400> 188
atgggatgga gctggacctt tctcttcctc ctgtcaggaa ctgcaggtgt cctctctgag 60
gtccaactgc aacagtctgg acctgaacta atgaagcctg gggcttcagt gaagatgtcc 120
tgcaaggctt ctggatatac attcactgac tacaacatgc actgggtgaa gcagaaccaa 180
ggaaagaccc tagaatggat aggagaaatt aatcctaaca gtggtggtgc tggctacaac 240
cagaagttca agggcaaggc cacattgact gtagacaagt cctccaccac agcctacatg 300
gagctccgca gcctgacatc tgaggactct gcagtctatt actgtgcaag attgggctac 360
gatgatatct acgacgactg gtacttcgat gtctggggcg cagggaccac ggtcaccgtc 420
tcctcagcca aaacgacacc cccatctgtc tatccactgg cccctggatc tgctgcccaa 480
actaactcca tggtgaccct gggatgcctg gtcaagggct atttccctga gccagtgaca 540
gtgacctgga actctggatc cctgtccagc ggtgtgcaca ccttcccagc tgtcctgcag 600
tctgacctct acactctgag cagctcagtg actgtcccct ccagcacctg gcccagcgag 660
accgtcacct gcaacgttgc ccacccggcc agcagcacca aggtggacaa gaaaattgtg 720
cccagggatt gtggttgtaa gccttgcata tgtacagtcc cagaagtatc atctgtcttc 780
atcttccccc caaagcccaa ggatgtgctc accattactc tgactcctaa ggtcacgtgt 840
gttgtggtag acatcagcaa ggatgatccc gaggtccagt tcagctggtt tgtagatgat 900
gtggaggtgc acacagctca gacgcaaccc cgggaggagc agttcaacag cactttccgc 960
tcagtcagtg aacttcccat catgcaccag gactggctca atggcaagga gttcaaatgc 1020
agggtcaaca gtgcagcttt ccctgccccc atcgagaaaa ccatctccaa aaccaaaggc 1080
agaccgaagg ctccacaggt gtacaccatt ccacctccca aggagcagat ggccaaggat 1140
aaagtcagtc tgacctgcat gataacagac ttcttccctg aagacattac tgtggagtgg 1200
cagtggaatg ggcagccagc ggagaactac aagaacactc agcccatcat ggacacagat 1260
ggctcttact tcatctacag caagctcaat gtgcagaaga gcaactggga ggcaggaaat 1320
actttcacct gctctgtgtt acatgagggc ctgcacaacc accatactga gaagagcctc 1380
tcccactctc ctggtaaatg a 1401
<210> 189
<211> 213
<212> PRT
<213> Mus musculus
<400> 189
Gln Ile Val Leu Ser Gln Ser Pro Ala Phe Leu Ser Val Ser Pro Gly
1 5 10 15
Asp Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Ile Ser Tyr Ile
20 25 30
His Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Arg Ser Trp Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Val Glu Ala Glu
65 70 75 80
Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asp Pro Leu Thr
85 90 95
Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 190
<211> 642
<212> DNA
<213> Mus musculus
<400> 190
caaattgttc tctcccagtc tccagcattc ctgtctgtat ctccagggga taaggtcaca 60
atgacttgca gggccagctc aagtataagt tacatacact ggtttcagca gaagccagga 120
tcctccccca gatcctggat ttatgccaca tccaacctgg cttctggagt ccctggtcgc 180
ttcagtggca gtgggtctgg gacctcttac tctctcacaa tcagcagagt ggaggctgag 240
gatgctgcca cttattactg ccagcagtgg agtagtgacc cactcacgtt cggtgctggg 300
accaagctgg agctgaaacg ggctgatgct gcaccaactg tatccatctt cccaccatcc 360
agtgagcagt taacatctgg aggtgcctca gtcgtgtgct tcttgaacaa cttctacccc 420
aaagacatca atgtcaagtg gaagattgat ggcagtgaac gacaaaatgg cgtcctgaac 480
agttggactg atcaggacag caaagacagc acctacagca tgagcagcac cctcacgttg 540
accaaggacg agtatgaacg acataacagc tatacctgtg aggccactca caagacatca 600
acttcaccca ttgtcaagag cttcaacagg aatgagtgtt ag 642
<210> 191
<211> 235
<212> PRT
<213> Mus musculus
<400> 191
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Ser
1 5 10 15
Val Ile Met Ser Arg Gly Gln Ile Val Leu Ser Gln Ser Pro Ala Phe
20 25 30
Leu Ser Val Ser Pro Gly Asp Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Ile Ser Tyr Ile His Trp Phe Gln Gln Lys Pro Gly Ser Ser
50 55 60
Pro Arg Ser Trp Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Gly Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile
85 90 95
Ser Arg Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asp Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys
115 120 125
Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu
130 135 140
Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe
145 150 155 160
Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg
165 170 175
Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu
195 200 205
Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser
210 215 220
Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 192
<211> 708
<212> DNA
<213> Mus musculus
<400> 192
atggattttc aagtgcagat tttcagcttc ctgctaatca gtgcttcagt cataatgtcc 60
agaggacaaa ttgttctctc ccagtctcca gcattcctgt ctgtatctcc aggggataag 120
gtcacaatga cttgcagggc cagctcaagt ataagttaca tacactggtt tcagcagaag 180
ccaggatcct cccccagatc ctggatttat gccacatcca acctggcttc tggagtccct 240
ggtcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagagtggag 300
gctgaggatg ctgccactta ttactgccag cagtggagta gtgacccact cacgttcggt 360
gctgggacca agctggagct gaaacgggct gatgctgcac caactgtatc catcttccca 420
ccatccagtg agcagttaac atctggaggt gcctcagtcg tgtgcttctt gaacaacttc 480
taccccaaag acatcaatgt caagtggaag attgatggca gtgaacgaca aaatggcgtc 540
ctgaacagtt ggactgatca ggacagcaaa gacagcacct acagcatgag cagcaccctc 600
acgttgacca aggacgagta tgaacgacat aacagctata cctgtgaggc cactcacaag 660
acatcaactt cacccattgt caagagcttc aacaggaatg agtgttag 708
<210> 193
<211> 445
<212> PRT
<213> Mus musculus
<400> 193
Glu Val Gln Leu Gln Gln Ser Gly Ala Asp Leu Val Gln Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Thr Ala Ser Gly Phe Asp Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala Pro Lys Phe
50 55 60
Pro Gly Lys Ala Thr Phe Thr Thr Asp Thr Ser Ser Asn Thr Ala Tyr
65 70 75 80
Leu Gln Leu Arg Gly Leu Thr Ser Glu Asp Thr Ala Ile Tyr Tyr Cys
85 90 95
Gly Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
180 185 190
Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
210 215 220
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
245 250 255
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln
260 265 270
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
290 295 300
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
305 310 315 320
Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
340 345 350
Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
355 360 365
Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
370 375 380
Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly
385 390 395 400
Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu
405 410 415
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
420 425 430
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 194
<211> 1338
<212> DNA
<213> Mus musculus
<400> 194
gaagttcagc tgcaacagtc tggggcagac cttgtgcagc caggggcctc agtcaaggtg 60
tcctgcacag cttctggctt cgacattaag gactactata tacactggat gaaacagagg 120
cctgaccagg gcctggagtg gattggaagg gttgatcctg acaatggtga gactgaattt 180
gccccgaagt tcccgggcaa ggccactttt acaacagaca catcctccaa cacagcctac 240
ctacaactca gaggcctgac atctgaggac actgccatct attactgtgg gagagaagac 300
tacgatggta cctacacctg gtttccttat tggggccaag ggactctggt cactgtctct 360
gcagccaaaa cgacaccccc atctgtctat ccactggccc ctggatctgc tgcccaaact 420
aactccatgg tgaccctggg atgcctggtc aagggctatt tccctgagcc agtgacagtg 480
acctggaact ctggatccct gtccagcggt gtgcacacct tcccagctgt cctgcagtct 540
gacctctaca ctctgagcag ctcagtgact gtcccctcca gcacctggcc cagcgagacc 600
gtcacctgca acgttgccca cccggccagc agcaccaagg tggacaagaa aattgtgccc 660
agggattgtg gttgtaagcc ttgcatatgt acagtcccag aagtatcatc tgtcttcatc 720
ttccccccaa agcccaagga tgtgctcacc attactctga ctcctaaggt cacgtgtgtt 780
gtggtagaca tcagcaagga tgatcccgag gtccagttca gctggtttgt agatgatgtg 840
gaggtgcaca cagctcagac gcaaccccgg gaggagcagt tcaacagcac tttccgctca 900
gtcagtgaac ttcccatcat gcaccaggac tggctcaatg gcaaggagtt caaatgcagg 960
gtcaacagtg cagctttccc tgcccccatc gagaaaacca tctccaaaac caaaggcaga 1020
ccgaaggctc cacaggtgta caccattcca cctcccaagg agcagatggc caaggataaa 1080
gtcagtctga cctgcatgat aacagacttc ttccctgaag acattactgt ggagtggcag 1140
tggaatgggc agccagcgga gaactacaag aacactcagc ccatcatgga cacagatggc 1200
tcttacttca tctacagcaa gctcaatgtg cagaagagca actgggaggc aggaaatact 1260
ttcacctgct ctgtgttaca tgagggcctg cacaaccacc atactgagaa gagcctctcc 1320
cactctcctg gtaaatga 1338
<210> 195
<211> 464
<212> PRT
<213> Mus musculus
<400> 195
Met Lys Cys Ser Trp Val Ile Phe Phe Leu Met Ala Val Val Thr Gly
1 5 10 15
Val Asn Ser Glu Val Gln Leu Gln Gln Ser Gly Ala Asp Leu Val Gln
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Thr Ala Ser Gly Phe Asp Ile
35 40 45
Lys Asp Tyr Tyr Ile His Trp Met Lys Gln Arg Pro Asp Gln Gly Leu
50 55 60
Glu Trp Ile Gly Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala
65 70 75 80
Pro Lys Phe Pro Gly Lys Ala Thr Phe Thr Thr Asp Thr Ser Ser Asn
85 90 95
Thr Ala Tyr Leu Gln Leu Arg Gly Leu Thr Ser Glu Asp Thr Ala Ile
100 105 110
Tyr Tyr Cys Gly Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr
130 135 140
Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn
145 150 155 160
Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val
195 200 205
Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val
210 215 220
Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg
225 230 235 240
Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser
245 250 255
Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu
260 265 270
Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro
275 280 285
Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala
290 295 300
Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val
305 310 315 320
Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe
325 330 335
Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr
340 345 350
Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile
355 360 365
Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys
370 375 380
Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp
385 390 395 400
Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp
405 410 415
Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser
420 425 430
Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly
435 440 445
Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 196
<211> 1395
<212> DNA
<213> Mus musculus
<400> 196
atgaaatgca gctgggtcat cttcttcctg atggcagtgg ttacaggggt caattcagaa 60
gttcagctgc aacagtctgg ggcagacctt gtgcagccag gggcctcagt caaggtgtcc 120
tgcacagctt ctggcttcga cattaaggac tactatatac actggatgaa acagaggcct 180
gaccagggcc tggagtggat tggaagggtt gatcctgaca atggtgagac tgaatttgcc 240
ccgaagttcc cgggcaaggc cacttttaca acagacacat cctccaacac agcctaccta 300
caactcagag gcctgacatc tgaggacact gccatctatt actgtgggag agaagactac 360
gatggtacct acacctggtt tccttattgg ggccaaggga ctctggtcac tgtctctgca 420
gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 480
tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 540
tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 600
ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 660
acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 720
gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 780
cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 840
gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 900
gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 960
agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 1020
aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 1080
aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 1140
agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 1200
aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 1260
tacttcatct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 1320
acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 1380
tctcctggta aatga 1395
<210> 197
<211> 214
<212> PRT
<213> Mus musculus
<400> 197
Asp Leu Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Phe Tyr Thr Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asn Tyr Ser Leu Thr Ile Thr Asn Leu Glu Gln
65 70 75 80
Asp Asp Ala Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala Ala
100 105 110
Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly
115 120 125
Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile
130 135 140
Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu
145 150 155 160
Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser
165 170 175
Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr
180 185 190
Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser
195 200 205
Phe Asn Arg Asn Glu Cys
210
<210> 198
<211> 645
<212> DNA
<213> Mus musculus
<400> 198
gatctccaga tgacacagac tacttcctcc ctgtctgcct ctctgggaga cagagtcacc 60
atcagttgca gggcaagtca ggacattagc aattatttaa actggtatca gcagaaacca 120
gatggaactg ttaagctcct gatcttctac acatcaacat tacagtcagg agtcccatcg 180
aggttcagtg gcagtgggtc tggaacaaat tattctctca ccattaccaa cctggagcaa 240
gatgatgctg ccacttactt ttgccaacag ggtgatacgc ttccgtacac gttcggaggg 300
gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 360
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 420
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 480
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 540
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 600
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 645
<210> 199
<211> 234
<212> PRT
<213> Mus musculus
<400> 199
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Ser Arg Cys Asp Leu Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val
50 55 60
Lys Leu Leu Ile Phe Tyr Thr Ser Thr Leu Gln Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asn Tyr Ser Leu Thr Ile Thr
85 90 95
Asn Leu Glu Gln Asp Asp Ala Ala Thr Tyr Phe Cys Gln Gln Gly Asp
100 105 110
Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
115 120 125
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
130 135 140
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
145 150 155 160
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
165 170 175
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
180 185 190
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
195 200 205
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
210 215 220
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230
<210> 200
<211> 705
<212> DNA
<213> Mus musculus
<400> 200
atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg ttccagatgt 60
gatctccaga tgacacagac tacttcctcc ctgtctgcct ctctgggaga cagagtcacc 120
atcagttgca gggcaagtca ggacattagc aattatttaa actggtatca gcagaaacca 180
gatggaactg ttaagctcct gatcttctac acatcaacat tacagtcagg agtcccatcg 240
aggttcagtg gcagtgggtc tggaacaaat tattctctca ccattaccaa cctggagcaa 300
gatgatgctg ccacttactt ttgccaacag ggtgatacgc ttccgtacac gttcggaggg 360
gggaccaagc tggaaataaa acgggctgat gctgcaccaa ctgtatccat cttcccacca 420
tccagtgagc agttaacatc tggaggtgcc tcagtcgtgt gcttcttgaa caacttctac 480
cccaaagaca tcaatgtcaa gtggaagatt gatggcagtg aacgacaaaa tggcgtcctg 540
aacagttgga ctgatcagga cagcaaagac agcacctaca gcatgagcag caccctcacg 600
ttgaccaagg acgagtatga acgacataac agctatacct gtgaggccac tcacaagaca 660
tcaacttcac ccattgtcaa gagcttcaac aggaatgagt gttag 705
<210> 201
<211> 447
<212> PRT
<213> Mus musculus
<400> 201
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Met Lys Gln Asn Gln Gly Lys Ser Leu Glu Trp Ile
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ser Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Tyr Tyr Gly Asn Tyr Glu Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys Thr Thr Pro
115 120 125
Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser
130 135 140
Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr
180 185 190
Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala
195 200 205
His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp
210 215 220
Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val
225 230 235 240
Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr
245 250 255
Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu
260 265 270
Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln
275 280 285
Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser
290 295 300
Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys
305 310 315 320
Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro
340 345 350
Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met
355 360 365
Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn
370 375 380
Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr
385 390 395 400
Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn
405 410 415
Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu
420 425 430
His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 202
<211> 1344
<212> DNA
<213> Mus musculus
<400> 202
gaggtccagt tgcaacagtc tggacctgaa ctaatgaagc ctggggcttc agtgaagatg 60
tcctgcaagg cttctggata cacattcact gactacaaca tgcactggat gaagcagaac 120
caaggaaaga gcctagagtg gataggagag attaatccta acagtggtgg ttctggttac 180
aaccagaagt tcaaaggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240
atggagctcc gcagcctgac atctgaggac tctgcagtct attactgtgc aagattgggc 300
tactatggta actacgagga ctggtatttc gatgtctggg gcgcagggac cacggtcacc 360
gtctcctctg ccaaaacgac acccccatct gtctatccac tggcccctgg atctgctgcc 420
caaactaact ccatggtgac cctgggatgc ctggtcaagg gctatttccc tgagccagtg 480
acagtgacct ggaactctgg atccctgtcc agcggtgtgc acaccttccc agctgtcctg 540
cagtctgacc tctacactct gagcagctca gtgactgtcc cctccagcac ctggcccagc 600
gagaccgtca cctgcaacgt tgcccacccg gccagcagca ccaaggtgga caagaaaatt 660
gtgcccaggg attgtggttg taagccttgc atatgtacag tcccagaagt atcatctgtc 720
ttcatcttcc ccccaaagcc caaggatgtg ctcaccatta ctctgactcc taaggtcacg 780
tgtgttgtgg tagacatcag caaggatgat cccgaggtcc agttcagctg gtttgtagat 840
gatgtggagg tgcacacagc tcagacgcaa ccccgggagg agcagttcaa cagcactttc 900
cgctcagtca gtgaacttcc catcatgcac caggactggc tcaatggcaa ggagttcaaa 960
tgcagggtca acagtgcagc tttccctgcc cccatcgaga aaaccatctc caaaaccaaa 1020
ggcagaccga aggctccaca ggtgtacacc attccacctc ccaaggagca gatggccaag 1080
gataaagtca gtctgacctg catgataaca gacttcttcc ctgaagacat tactgtggag 1140
tggcagtgga atgggcagcc agcggagaac tacaagaaca ctcagcccat catggacaca 1200
gatggctctt acttcatcta cagcaagctc aatgtgcaga agagcaactg ggaggcagga 1260
aatactttca cctgctctgt gttacatgag ggcctgcaca accaccatac tgagaagagc 1320
ctctcccact ctcctggtaa atga 1344
<210> 203
<211> 466
<212> PRT
<213> Mus musculus
<400> 203
Met Gly Trp Ser Trp Thr Phe Leu Phe Leu Leu Ser Gly Thr Ser Gly
1 5 10 15
Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Met Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Asn Met His Trp Met Lys Gln Asn Gln Gly Lys Ser Leu
50 55 60
Glu Trp Ile Gly Glu Ile Asn Pro Asn Ser Gly Gly Ser Gly Tyr Asn
65 70 75 80
Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Leu Gly Tyr Tyr Gly Asn Tyr Glu Asp Trp Tyr
115 120 125
Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ala Lys
130 135 140
Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln
145 150 155 160
Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro
165 170 175
Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val
180 185 190
His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser
195 200 205
Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys
210 215 220
Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val
225 230 235 240
Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val
245 250 255
Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile
260 265 270
Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp
275 280 285
Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His
290 295 300
Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr
355 360 365
Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu
370 375 380
Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp
385 390 395 400
Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile
405 410 415
Met Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln
420 425 430
Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His
435 440 445
Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro
450 455 460
Gly Lys
465
<210> 204
<211> 1401
<212> DNA
<213> Mus musculus
<400> 204
atgggatgga gctggacctt tctcttcctc ctgtcaggaa cttcgggtgt cctctctgag 60
gtccagttgc aacagtctgg acctgaacta atgaagcctg gggcttcagt gaagatgtcc 120
tgcaaggctt ctggatacac attcactgac tacaacatgc actggatgaa gcagaaccaa 180
ggaaagagcc tagagtggat aggagagatt aatcctaaca gtggtggttc tggttacaac 240
cagaagttca aaggcaaggc cacattgact gtagacaagt cctccagcac agcctacatg 300
gagctccgca gcctgacatc tgaggactct gcagtctatt actgtgcaag attgggctac 360
tatggtaact acgaggactg gtatttcgat gtctggggcg cagggaccac ggtcaccgtc 420
tcctctgcca aaacgacacc cccatctgtc tatccactgg cccctggatc tgctgcccaa 480
actaactcca tggtgaccct gggatgcctg gtcaagggct atttccctga gccagtgaca 540
gtgacctgga actctggatc cctgtccagc ggtgtgcaca ccttcccagc tgtcctgcag 600
tctgacctct acactctgag cagctcagtg actgtcccct ccagcacctg gcccagcgag 660
accgtcacct gcaacgttgc ccacccggcc agcagcacca aggtggacaa gaaaattgtg 720
cccagggatt gtggttgtaa gccttgcata tgtacagtcc cagaagtatc atctgtcttc 780
atcttccccc caaagcccaa ggatgtgctc accattactc tgactcctaa ggtcacgtgt 840
gttgtggtag acatcagcaa ggatgatccc gaggtccagt tcagctggtt tgtagatgat 900
gtggaggtgc acacagctca gacgcaaccc cgggaggagc agttcaacag cactttccgc 960
tcagtcagtg aacttcccat catgcaccag gactggctca atggcaagga gttcaaatgc 1020
agggtcaaca gtgcagcttt ccctgccccc atcgagaaaa ccatctccaa aaccaaaggc 1080
agaccgaagg ctccacaggt gtacaccatt ccacctccca aggagcagat ggccaaggat 1140
aaagtcagtc tgacctgcat gataacagac ttcttccctg aagacattac tgtggagtgg 1200
cagtggaatg ggcagccagc ggagaactac aagaacactc agcccatcat ggacacagat 1260
ggctcttact tcatctacag caagctcaat gtgcagaaga gcaactggga ggcaggaaat 1320
actttcacct gctctgtgtt acatgagggc ctgcacaacc accatactga gaagagcctc 1380
tcccactctc ctggtaaatg a 1401
<210> 205
<211> 215
<212> PRT
<213> Mus musculus
<400> 205
Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly
1 5 10 15
Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Thr Ser Ser
20 25 30
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu
65 70 75 80
Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Phe Phe Pro
85 90 95
Ser Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg Ala Asp Ala
100 105 110
Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser
115 120 125
Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp
130 135 140
Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val
145 150 155 160
Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met
165 170 175
Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser
180 185 190
Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys
195 200 205
Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 206
<211> 645
<212> DNA
<213> Mus musculus
<400> 206
cagattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60
atgacctgca gggccagctc aagtgtaact tccagttact tgaactggta ccagcagaag 120
ccaggatctt cccccaaact ctggatttat agcacatcca acctggcttc aggagtccca 180
gctcgcttca gtggcagtgg gtctgggacc tcttactctc tcacaatcag cagtgtggag 240
gctgaggatg ctgccactta ttactgccag cagtatgatt ttttcccatc gacgttcggt 300
ggaggcacca agctggaaat caagcgggct gatgctgcac caactgtatc catcttccca 360
ccatccagtg agcagttaac atctggaggt gcctcagtcg tgtgcttctt gaacaacttc 420
taccccaaag acatcaatgt caagtggaag attgatggca gtgaacgaca aaatggcgtc 480
ctgaacagtt ggactgatca ggacagcaaa gacagcacct acagcatgag cagcaccctc 540
acgttgacca aggacgagta tgaacgacat aacagctata cctgtgaggc cactcacaag 600
acatcaactt cacccatcgt caagagcttc aacaggaatg agtgt 645
<210> 207
<211> 237
<212> PRT
<213> Mus musculus
<400> 207
Met Asp Ser Gln Val Gln Ile Phe Ser Phe Leu Leu Ile Ser Ala Leu
1 5 10 15
Val Lys Met Ser Arg Gly Gln Ile Val Leu Thr Gln Ser Pro Ala Ile
20 25 30
Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Thr Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
50 55 60
Ser Ser Pro Lys Leu Trp Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly
65 70 75 80
Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu
85 90 95
Thr Ile Ser Ser Val Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln
100 105 110
Gln Tyr Asp Phe Phe Pro Ser Thr Phe Gly Gly Gly Thr Lys Leu Glu
115 120 125
Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser
130 135 140
Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn
145 150 155 160
Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser
165 170 175
Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu
195 200 205
Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser
210 215 220
Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 208
<211> 711
<212> DNA
<213> Mus musculus
<400> 208
atggattctc aagtgcagat tttcagcttc cttctaatca gtgccttagt caaaatgtcc 60
agaggacaga ttgttctcac ccagtctcca gcaatcatgt ctgcatctcc aggggagaag 120
gtcaccatga cctgcagggc cagctcaagt gtaacttcca gttacttgaa ctggtaccag 180
cagaagccag gatcttcccc caaactctgg atttatagca catccaacct ggcttcagga 240
gtcccagctc gcttcagtgg cagtgggtct gggacctctt actctctcac aatcagcagt 300
gtggaggctg aggatgctgc cacttattac tgccagcagt atgatttttt cccatcgacg 360
ttcggtggag gcaccaagct ggaaatcaag cgggctgatg ctgcaccaac tgtatccatc 420
ttcccaccat ccagtgagca gttaacatct ggaggtgcct cagtcgtgtg cttcttgaac 480
aacttctacc ccaaagacat caatgtcaag tggaagattg atggcagtga acgacaaaat 540
ggcgtcctga acagttggac tgatcaggac agcaaagaca gcacctacag catgagcagc 600
accctcacgt tgaccaagga cgagtatgaa cgacataaca gctatacctg tgaggccact 660
cacaagacat caacttcacc catcgtcaag agcttcaaca ggaatgagtg t 711
<210> 209
<211> 445
<212> PRT
<213> Mus musculus
<400> 209
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Lys Gln Ser His Gly Glu Ser Leu Glu Trp Ile
35 40 45
Gly Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn His Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr
65 70 75 80
Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser
115 120 125
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
130 135 140
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
180 185 190
Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro
195 200 205
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
210 215 220
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
225 230 235 240
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
245 250 255
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln
260 265 270
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln
275 280 285
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
290 295 300
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
305 310 315 320
Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
340 345 350
Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
355 360 365
Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
370 375 380
Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly
385 390 395 400
Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu
405 410 415
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
420 425 430
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440 445
<210> 210
<211> 1335
<212> DNA
<213> Mus musculus
<400> 210
gaggtccagc tgcaacaatc tggacctgag ctggtgaagc ctggggcttc agtgaagatg 60
tcctgtaagg cttctggata cacattcact gactactaca tgaactgggt gaagcagagc 120
catggagaga gccttgagtg gattggagat attaatcctt acaacgatga tactacctac 180
aaccacaagt tcaagggcaa ggccacattg actgtagaca aatcctccaa cacagcctac 240
atgcagctca acagcctgac atctgaggac tctgcagtct attactgtgc aagagagacg 300
gccgttatta ctacgaatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360
tcagccaaaa cgacaccccc atctgtctat ccactggccc ctggatctgc tgcccaaact 420
aactccatgg tgaccctggg atgcctggtc aagggctatt tccctgagcc agtgacagtg 480
acctggaact ctggatccct gtccagcggt gtgcacacct tcccagctgt cctgcagtct 540
gacctctaca ctctgagcag ctcagtgact gtcccctcca gcacctggcc cagcgagacc 600
gtcacctgca acgttgccca cccggccagc agcaccaagg tggacaagaa aattgtgccc 660
agggattgtg gttgtaagcc ttgcatatgt acagtcccag aagtatcatc tgtcttcatc 720
ttccccccaa agcccaagga tgtgctcacc attactctga ctcctaaggt cacgtgtgtt 780
gtggtagaca tcagcaagga tgatcccgag gtccagttca gctggtttgt agatgatgtg 840
gaggtgcaca cagctcagac gcaaccccgg gaggagcagt tcaacagcac tttccgctca 900
gtcagtgaac ttcccatcat gcaccaggac tggctcaatg gcaaggagtt caaatgcagg 960
gtcaacagtg cagctttccc tgcccccatc gagaaaacca tctccaaaac caaaggcaga 1020
ccgaaggctc cacaggtgta caccattcca cctcccaagg agcagatggc caaggataaa 1080
gtcagtctga cctgcatgat aacagacttc ttccctgaag acattactgt ggagtggcag 1140
tggaatgggc agccagcgga gaactacaag aacactcagc ccatcatgga cacagatggc 1200
tcttacttca tctacagcaa gctcaatgtg cagaagagca actgggaggc aggaaatact 1260
ttcacctgct ctgtgttaca tgagggcctg cacaaccacc atactgagaa gagcctctcc 1320
cactctcctg gtaaa 1335
<210> 211
<211> 464
<212> PRT
<213> Mus musculus
<400> 211
Met Gly Trp Asn Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val Tyr Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Tyr Met Asn Trp Val Lys Gln Ser His Gly Glu Ser Leu
50 55 60
Glu Trp Ile Gly Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn
65 70 75 80
His Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn
85 90 95
Thr Ala Tyr Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr
130 135 140
Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn
145 150 155 160
Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val
195 200 205
Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val
210 215 220
Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg
225 230 235 240
Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser
245 250 255
Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu
260 265 270
Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro
275 280 285
Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala
290 295 300
Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val
305 310 315 320
Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe
325 330 335
Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr
340 345 350
Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile
355 360 365
Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys
370 375 380
Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp
385 390 395 400
Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp
405 410 415
Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser
420 425 430
Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly
435 440 445
Leu His Asn His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 212
<211> 1392
<212> DNA
<213> Mus musculus
<400> 212
atgggatgga actggatctt tctcttcctc ttgtcaggaa ctgcaggtgt ctactctgag 60
gtccagctgc aacaatctgg acctgagctg gtgaagcctg gggcttcagt gaagatgtcc 120
tgtaaggctt ctggatacac attcactgac tactacatga actgggtgaa gcagagccat 180
ggagagagcc ttgagtggat tggagatatt aatccttaca acgatgatac tacctacaac 240
cacaagttca agggcaaggc cacattgact gtagacaaat cctccaacac agcctacatg 300
cagctcaaca gcctgacatc tgaggactct gcagtctatt actgtgcaag agagacggcc 360
gttattacta cgaatgctat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 420
gccaaaacga cacccccatc tgtctatcca ctggcccctg gatctgctgc ccaaactaac 480
tccatggtga ccctgggatg cctggtcaag ggctatttcc ctgagccagt gacagtgacc 540
tggaactctg gatccctgtc cagcggtgtg cacaccttcc cagctgtcct gcagtctgac 600
ctctacactc tgagcagctc agtgactgtc ccctccagca cctggcccag cgagaccgtc 660
acctgcaacg ttgcccaccc ggccagcagc accaaggtgg acaagaaaat tgtgcccagg 720
gattgtggtt gtaagccttg catatgtaca gtcccagaag tatcatctgt cttcatcttc 780
cccccaaagc ccaaggatgt gctcaccatt actctgactc ctaaggtcac gtgtgttgtg 840
gtagacatca gcaaggatga tcccgaggtc cagttcagct ggtttgtaga tgatgtggag 900
gtgcacacag ctcagacgca accccgggag gagcagttca acagcacttt ccgctcagtc 960
agtgaacttc ccatcatgca ccaggactgg ctcaatggca aggagttcaa atgcagggtc 1020
aacagtgcag ctttccctgc ccccatcgag aaaaccatct ccaaaaccaa aggcagaccg 1080
aaggctccac aggtgtacac cattccacct cccaaggagc agatggccaa ggataaagtc 1140
agtctgacct gcatgataac agacttcttc cctgaagaca ttactgtgga gtggcagtgg 1200
aatgggcagc cagcggagaa ctacaagaac actcagccca tcatggacac agatggctct 1260
tacttcatct acagcaagct caatgtgcag aagagcaact gggaggcagg aaatactttc 1320
acctgctctg tgttacatga gggcctgcac aaccaccata ctgagaagag cctctcccac 1380
tctcctggta aa 1392
<210> 213
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 213
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Thr Ser Ser
20 25 30
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Phe Phe Pro
85 90 95
Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 214
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 214
gacatccagc tgacccagag ccccagcttc ctttccgcat ccgttggtga ccgagtaaca 60
atcacatgcc gcgcctcatc ttcagttaca tcttcttatc ttaattggta tcaacaaaaa 120
ccaggaaaag cacctaaact tcttatatac tctacatcta atctcgcatc aggagttccc 180
tctcgatttt caggatctgg atcaggcaca gaatttacac ttactatatc atcactccaa 240
ccagaagact tcgccactta ttactgccaa caatacgatt tttttccaag cacattcgga 300
ggaggtacaa aagtagaaat caagcgtacg gtggctgcac catctgtctt catcttcccg 360
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645
<210> 215
<211> 237
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 215
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Ser Ser Val Thr Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly
50 55 60
Lys Ala Pro Lys Leu Leu Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly
65 70 75 80
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu
85 90 95
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
100 105 110
Gln Tyr Asp Phe Phe Pro Ser Thr Phe Gly Gly Gly Thr Lys Val Glu
115 120 125
Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser
130 135 140
Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
145 150 155 160
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
165 170 175
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
195 200 205
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
210 215 220
Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 216
<211> 711
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 216
atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct cccaggtgcc 60
agatgtgaca tccagctgac ccagagcccc agcttccttt ccgcatccgt tggtgaccga 120
gtaacaatca catgccgcgc ctcatcttca gttacatctt cttatcttaa ttggtatcaa 180
caaaaaccag gaaaagcacc taaacttctt atatactcta catctaatct cgcatcagga 240
gttccctctc gattttcagg atctggatca ggcacagaat ttacacttac tatatcatca 300
ctccaaccag aagacttcgc cacttattac tgccaacaat acgatttttt tccaagcaca 360
ttcggaggag gtacaaaagt agaaatcaag cgtacggtgg ctgcaccatc tgtcttcatc 420
ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 480
aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 540
aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 600
accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 660
catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 711
<210> 217
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 217
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn His Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
210 215 220
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
290 295 300
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 218
<211> 1341
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 218
gaggtgcagc tggtgcagag cggcgccgag gtcaagaaac ctggagcaag cgtaaaggtt 60
agttgcaaag catctggata cacatttacc gactactaca tgaattgggt acgacaagcc 120
cctggacaaa gacttgaatg gatgggagac attaaccctt ataacgacga cactacatac 180
aatcataaat ttaaaggaag agttacaatt acaagagata catccgcatc aaccgcctat 240
atggaacttt cctcattgag atctgaagac actgctgttt attactgtgc aagagaaact 300
gccgttatta ctactaacgc tatggattac tggggtcaag gaaccactgt taccgtctct 360
agtgcctcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 420
gagagcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgctct gaccagcggc gtgcacacct tcccagctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcaactt cggcacccag 600
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gacagttgag 660
cgcaaatgtt gtgtcgagtg cccaccgtgc ccagcaccac ctgtggcagg accgtcagtc 720
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcacg 780
tgcgtggtgg tggacgtgag ccacgaagac cccgaggtcc agttcaactg gtacgtggac 840
ggcgtggagg tgcataatgc caagacaaag ccacgggagg agcagttcaa cagcacgttc 900
cgtgtggtca gcgtcctcac cgttgtgcac caggactggc tgaacggcaa ggagtacaag 960
tgcaaggtct ccaacaaagg cctcccagcc cccatcgaga aaaccatctc caaaaccaaa 1020
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080
aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140
tgggagagca atgggcagcc ggagaacaac tacaagacca cacctcccat gctggactcc 1200
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320
ctctccctgt ctccgggtaa a 1341
<210> 219
<211> 466
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 219
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe
35 40 45
Thr Asp Tyr Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu
50 55 60
Glu Trp Met Gly Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn
65 70 75 80
His Lys Phe Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp
115 120 125
Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu
145 150 155 160
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn
210 215 220
Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg
225 230 235 240
Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 220
<211> 1398
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 220
atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactccgag 60
gtgcagctgg tgcagagcgg cgccgaggtc aagaaacctg gagcaagcgt aaaggttagt 120
tgcaaagcat ctggatacac atttaccgac tactacatga attgggtacg acaagcccct 180
ggacaaagac ttgaatggat gggagacatt aacccttata acgacgacac tacatacaat 240
cataaattta aaggaagagt tacaattaca agagatacat ccgcatcaac cgcctatatg 300
gaactttcct cattgagatc tgaagacact gctgtttatt actgtgcaag agaaactgcc 360
gttattacta ctaacgctat ggattactgg ggtcaaggaa ccactgttac cgtctctagt 420
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 480
agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 660
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 720
aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 840
gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 900
gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 960
gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 1020
aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1080
cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1260
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380
tccctgtctc cgggtaaa 1398
<210> 221
<211> 215
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 221
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Val Ser Ser Thr Ile Ser Ser Asn
20 25 30
His Leu His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu
35 40 45
Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala
100 105 110
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser
115 120 125
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu
130 135 140
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser
145 150 155 160
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu
165 170 175
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val
180 185 190
Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys
195 200 205
Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 222
<211> 645
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 222
gacatccaga tgacccagtc tccatcctcc ctctcagcat ccgtaggcga tagagttaca 60
ataacatgca gcgtatcatc aactatatca tcaaatcatc ttcattggtt ccaacagaaa 120
cccggcaaag cacctaaatc acttatatac ggcacatcaa atctcgcatc aggcgttcct 180
tcaagatttt caggctctgg ctcaggcacc gactttactc ttacaatatc ctccctccaa 240
cccgaagact tcgcaaccta ttactgtcaa caatggtcct catatccact cacatttggc 300
ggcggcacaa aagtagaaat taaacgtacg gtggctgcac catctgtctt catcttcccg 360
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 420
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 480
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 540
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 600
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 645
<210> 223
<211> 237
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 223
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Val Ser
35 40 45
Ser Thr Ile Ser Ser Asn His Leu His Trp Phe Gln Gln Lys Pro Gly
50 55 60
Lys Ala Pro Lys Ser Leu Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly
65 70 75 80
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
85 90 95
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
100 105 110
Gln Trp Ser Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu
115 120 125
Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser
130 135 140
Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
145 150 155 160
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
165 170 175
Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
180 185 190
Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
195 200 205
Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
210 215 220
Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 224
<211> 711
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 224
atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60
agatgtgaca tccagatgac ccagtctcca tcctccctct cagcatccgt aggcgataga 120
gttacaataa catgcagcgt atcatcaact atatcatcaa atcatcttca ttggttccaa 180
cagaaacccg gcaaagcacc taaatcactt atatacggca catcaaatct cgcatcaggc 240
gttccttcaa gattttcagg ctctggctca ggcaccgact ttactcttac aatatcctcc 300
ctccaacccg aagacttcgc aacctattac tgtcaacaat ggtcctcata tccactcaca 360
tttggcggcg gcacaaaagt agaaattaaa cgtacggtgg ctgcaccatc tgtcttcatc 420
ttcccgccat ctgatgagca gttgaaatct ggaactgcct ctgttgtgtg cctgctgaat 480
aacttctatc ccagagaggc caaagtacag tggaaggtgg ataacgccct ccaatcgggt 540
aactcccagg agagtgtcac agagcaggac agcaaggaca gcacctacag cctcagcagc 600
accctgacgc tgagcaaagc agactacgag aaacacaaag tctacgcctg cgaagtcacc 660
catcagggcc tgagctcgcc cgtcacaaag agcttcaaca ggggagagtg t 711
<210> 225
<211> 451
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 225
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Phe Asn Ile Lys Asp Phe
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asn Gly Asp Thr Leu Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Lys Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ala Asp Tyr Phe His Asp Gly Thr Ser Tyr Trp Tyr Phe
100 105 110
Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
130 135 140
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
195 200 205
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
210 215 220
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
290 295 300
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 226
<211> 1353
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 226
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctgactt caacattaaa gacttctatc tacactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gattggaagg attgatcctg agaatggtga tactttatat 180
gacccgaagt tccaggacaa ggtcaccatg accacagaca cgtccaccag cacagcctac 240
atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagaggcg 300
gattatttcc acgatggtac ctcctactgg tacttcgatg tctggggccg tggcaccctg 360
gtcaccgtct ctagtgcctc caccaagggc ccatcggtct tccccctggc gccctgctcc 420
aggagcacct ccgagagcac agcggccctg ggctgcctgg tcaaggacta cttccccgaa 480
ccggtgacgg tgtcgtggaa ctcaggcgct ctgaccagcg gcgtgcacac cttcccagct 540
gtcctacagt cctcaggact ctactccctc agcagcgtgg tgaccgtgcc ctccagcaac 600
ttcggcaccc agacctacac ctgcaacgta gatcacaagc ccagcaacac caaggtggac 660
aagacagttg agcgcaaatg ttgtgtcgag tgcccaccgt gcccagcacc acctgtggca 720
ggaccgtcag tcttcctctt ccccccaaaa cccaaggaca ccctcatgat ctcccggacc 780
cctgaggtca cgtgcgtggt ggtggacgtg agccacgaag accccgaggt ccagttcaac 840
tggtacgtgg acggcgtgga ggtgcataat gccaagacaa agccacggga ggagcagttc 900
aacagcacgt tccgtgtggt cagcgtcctc accgttgtgc accaggactg gctgaacggc 960
aaggagtaca agtgcaaggt ctccaacaaa ggcctcccag cccccatcga gaaaaccatc 1020
tccaaaacca aagggcagcc ccgagaacca caggtgtaca ccctgccccc atcccgggag 1080
gagatgacca agaaccaggt cagcctgacc tgcctggtca aaggcttcta ccccagcgac 1140
atcgccgtgg agtgggagag caatgggcag ccggagaaca actacaagac cacacctccc 1200
atgctggact ccgacggctc cttcttcctc tacagcaagc tcaccgtgga caagagcagg 1260
tggcagcagg ggaacgtctt ctcatgctcc gtgatgcatg aggctctgca caaccactac 1320
acgcagaaga gcctctccct gtctccgggt aaa 1353
<210> 227
<211> 470
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 227
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Asp Phe Asn Ile
35 40 45
Lys Asp Phe Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Arg Ile Asp Pro Glu Asn Gly Asp Thr Leu Tyr Asp
65 70 75 80
Pro Lys Phe Gln Asp Lys Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Ala Asp Tyr Phe His Asp Gly Thr Ser Tyr
115 120 125
Trp Tyr Phe Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
130 135 140
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
145 150 155 160
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
165 170 175
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
180 185 190
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
195 200 205
Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
210 215 220
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
225 230 235 240
Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro
245 250 255
Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
260 265 270
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
275 280 285
Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
290 295 300
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
305 310 315 320
Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
325 330 335
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
340 345 350
Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu
355 360 365
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn
370 375 380
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
385 390 395 400
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
405 410 415
Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys
420 425 430
Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys
435 440 445
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
450 455 460
Ser Leu Ser Pro Gly Lys
465 470
<210> 228
<211> 1410
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 228
atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactccgag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctgacttcaa cattaaagac ttctatctac actgggtgcg acaggcccct 180
ggacaagggc ttgagtggat tggaaggatt gatcctgaga atggtgatac tttatatgac 240
ccgaagttcc aggacaaggt caccatgacc acagacacgt ccaccagcac agcctacatg 300
gagctgagga gcctgagatc tgacgacacg gccgtgtatt actgtgcgag agaggcggat 360
tatttccacg atggtacctc ctactggtac ttcgatgtct ggggccgtgg caccctggtc 420
accgtctcta gtgcctccac caagggccca tcggtcttcc ccctggcgcc ctgctccagg 480
agcacctccg agagcacagc ggccctgggc tgcctggtca aggactactt ccccgaaccg 540
gtgacggtgt cgtggaactc aggcgctctg accagcggcg tgcacacctt cccagctgtc 600
ctacagtcct caggactcta ctccctcagc agcgtggtga ccgtgccctc cagcaacttc 660
ggcacccaga cctacacctg caacgtagat cacaagccca gcaacaccaa ggtggacaag 720
acagttgagc gcaaatgttg tgtcgagtgc ccaccgtgcc cagcaccacc tgtggcagga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 840
gaggtcacgt gcgtggtggt ggacgtgagc cacgaagacc ccgaggtcca gttcaactgg 900
tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cacgggagga gcagttcaac 960
agcacgttcc gtgtggtcag cgtcctcacc gttgtgcacc aggactggct gaacggcaag 1020
gagtacaagt gcaaggtctc caacaaaggc ctcccagccc ccatcgagaa aaccatctcc 1080
aaaaccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 1140
atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctaccc cagcgacatc 1200
gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac acctcccatg 1260
ctggactccg acggctcctt cttcctctac agcaagctca ccgtggacaa gagcaggtgg 1320
cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 1380
cagaagagcc tctccctgtc tccgggtaaa 1410
<210> 229
<211> 213
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 229
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Ile Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asp Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 230
<211> 639
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 230
gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgca gggccagctc aagtataagt tacatacact ggtatcagca aaaaccaggg 120
aaagccccta agctcctgat ctatgccaca tccaacctgg cttctggggt cccatcaagg 180
ttcagcggca gtggatctgg gacagaattc actctcacaa tcagcagcct gcagcctgaa 240
gattttgcaa cttattactg tcagcagtgg agtagtgacc cactcacgtt cggcggaggg 300
accaaggtgg agatcaaacg tacggtggct gcaccatctg tcttcatctt cccgccatct 360
gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420
agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480
agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540
agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600
agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639
<210> 231
<211> 235
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 231
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Ser Ser Ile Ser Tyr Ile His Trp Tyr Gln Gln Lys Pro Gly Lys Ala
50 55 60
Pro Lys Leu Leu Ile Tyr Ala Thr Ser Asn Leu Ala Ser Gly Val Pro
65 70 75 80
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile
85 90 95
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp
100 105 110
Ser Ser Asp Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 232
<211> 705
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 232
atggacatga gggtccccgc tcagctcctg gggctcctgc tgctctggct cccaggtgcc 60
agatgtgaca tccagttgac ccagtctcca tccttcctgt ctgcatctgt aggagacaga 120
gtcaccatca cttgcagggc cagctcaagt ataagttaca tacactggta tcagcaaaaa 180
ccagggaaag cccctaagct cctgatctat gccacatcca acctggcttc tggggtccca 240
tcaaggttca gcggcagtgg atctgggaca gaattcactc tcacaatcag cagcctgcag 300
cctgaagatt ttgcaactta ttactgtcag cagtggagta gtgacccact cacgttcggc 360
ggagggacca aggtggagat caaacgtacg gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 233
<211> 447
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 233
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala Pro Lys Phe
50 55 60
Pro Gly Lys Val Thr Met Thr Thr Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
210 215 220
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
290 295 300
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 234
<211> 1341
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 234
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggatt cgacattaag gactactata tacactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatcggaagg gttgatcctg acaatggtga gactgaattt 180
gccccgaagt tcccgggcaa ggtcaccatg accacagaca cgtccatcag cacagcctac 240
atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagaagac 300
tacgatggta cctacacctg gtttccttat tggggccaag ggactctggt caccgtctct 360
agtgcctcca ccaagggccc atcggtcttc cccctggcgc cctgctccag gagcacctcc 420
gagagcacag cggccctggg ctgcctggtc aaggactact tccccgaacc ggtgacggtg 480
tcgtggaact caggcgctct gaccagcggc gtgcacacct tcccagctgt cctacagtcc 540
tcaggactct actccctcag cagcgtggtg accgtgccct ccagcaactt cggcacccag 600
acctacacct gcaacgtaga tcacaagccc agcaacacca aggtggacaa gacagttgag 660
cgcaaatgtt gtgtcgagtg cccaccgtgc ccagcaccac ctgtggcagg accgtcagtc 720
ttcctcttcc ccccaaaacc caaggacacc ctcatgatct cccggacccc tgaggtcacg 780
tgcgtggtgg tggacgtgag ccacgaagac cccgaggtcc agttcaactg gtacgtggac 840
ggcgtggagg tgcataatgc caagacaaag ccacgggagg agcagttcaa cagcacgttc 900
cgtgtggtca gcgtcctcac cgttgtgcac caggactggc tgaacggcaa ggagtacaag 960
tgcaaggtct ccaacaaagg cctcccagcc cccatcgaga aaaccatctc caaaaccaaa 1020
gggcagcccc gagaaccaca ggtgtacacc ctgcccccat cccgggagga gatgaccaag 1080
aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 1140
tgggagagca atgggcagcc ggagaacaac tacaagacca cacctcccat gctggactcc 1200
gacggctcct tcttcctcta cagcaagctc accgtggaca agagcaggtg gcagcagggg 1260
aacgtcttct catgctccgt gatgcatgag gctctgcaca accactacac gcagaagagc 1320
ctctccctgt ctccgggtaa a 1341
<210> 235
<211> 466
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 235
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile
35 40 45
Lys Asp Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala
65 70 75 80
Pro Lys Phe Pro Gly Lys Val Thr Met Thr Thr Asp Thr Ser Ile Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro
115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys
130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu
145 150 155 160
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
165 170 175
Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190
Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205
Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn
210 215 220
Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg
225 230 235 240
Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly
245 250 255
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
260 265 270
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
290 295 300
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320
Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys
325 330 335
Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu
340 345 350
Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
355 360 365
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
370 375 380
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
385 390 395 400
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met
405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
435 440 445
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
450 455 460
Gly Lys
465
<210> 236
<211> 1398
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 236
atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactccgag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg gggcctcagt gaaggtctcc 120
tgcaaggctt ctggattcga cattaaggac tactatatac actgggtgcg acaggcccct 180
ggacaagggc ttgagtggat cggaagggtt gatcctgaca atggtgagac tgaatttgcc 240
ccgaagttcc cgggcaaggt caccatgacc acagacacgt ccatcagcac agcctacatg 300
gagctgagca ggctgagatc tgacgacacg gccgtgtatt actgtgcgag agaagactac 360
gatggtacct acacctggtt tccttattgg ggccaaggga ctctggtcac cgtctctagt 420
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 480
agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 600
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 660
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 720
aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 840
gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 900
gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 960
gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 1020
aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1080
cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1260
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1320
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1380
tccctgtctc cgggtaaa 1398
<210> 237
<211> 7
<212> PRT
<213> Mus musculus
<400> 237
Gly Thr Ser Asn Leu Ala Ser
1 5
<210> 238
<211> 8
<212> PRT
<213> Mus musculus
<400> 238
Gln Gln Trp Thr Thr Thr Tyr Thr
1 5
<210> 239
<211> 11
<212> PRT
<213> Mus musculus
<400> 239
Arg Ala Ser Gln Asp Ile Ser Ser Tyr Leu Asn
1 5 10
<210> 240
<211> 7
<212> PRT
<213> Mus musculus
<400> 240
Ser Thr Ser Arg Leu Asn Ser
1 5
<210> 241
<211> 8
<212> PRT
<213> Mus musculus
<400> 241
Gln Gln Asp Ile Lys His Pro Thr
1 5
<210> 242
<211> 11
<212> PRT
<213> Mus musculus
<400> 242
Lys Ala Ser Gln Asp Val Phe Thr Ala Val Ala
1 5 10
<210> 243
<211> 7
<212> PRT
<213> Mus musculus
<400> 243
Trp Ala Ser Thr Arg His Thr
1 5
<210> 244
<211> 9
<212> PRT
<213> Mus musculus
<400> 244
Gln Gln Tyr Ser Ser Tyr Pro Leu Thr
1 5
<210> 245
<211> 5
<212> PRT
<213> Mus musculus
<400> 245
Asp Tyr Asn Met His
1 5
<210> 246
<211> 17
<212> PRT
<213> Mus musculus
<400> 246
Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 247
<211> 14
<212> PRT
<213> Mus musculus
<400> 247
Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
1 5 10
<210> 248
<211> 5
<212> PRT
<213> Mus musculus
<400> 248
Asp Tyr Asn Met His
1 5
<210> 249
<211> 17
<212> PRT
<213> Mus musculus
<400> 249
Glu Ile Asn Pro Asn Ser Gly Gly Ser Gly Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 250
<211> 14
<212> PRT
<213> Mus musculus
<400> 250
Leu Val Tyr Asp Gly Ser Tyr Glu Asp Trp Tyr Phe Asp Val
1 5 10
<210> 251
<211> 5
<212> PRT
<213> Mus musculus
<400> 251
Asp Tyr Asn Met His
1 5
<210> 252
<211> 17
<212> PRT
<213> Mus musculus
<400> 252
Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Gln Phe Lys
1 5 10 15
Gly
<210> 253
<211> 14
<212> PRT
<213> Mus musculus
<400> 253
Leu Gly Tyr Val Gly Asn Tyr Glu Asp Trp Tyr Phe Asp Val
1 5 10
<210> 254
<211> 5
<212> PRT
<213> Mus musculus
<400> 254
Asp Tyr Asn Met His
1 5
<210> 255
<211> 17
<212> PRT
<213> Mus musculus
<400> 255
Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 256
<211> 14
<212> PRT
<213> Mus musculus
<400> 256
Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
1 5 10
<210> 257
<211> 5
<212> PRT
<213> Mus musculus
<400> 257
Asp Tyr Asn Met His
1 5
<210> 258
<211> 17
<212> PRT
<213> Mus musculus
<400> 258
Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 259
<211> 14
<212> PRT
<213> Mus musculus
<400> 259
Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
1 5 10
<210> 260
<211> 5
<212> PRT
<213> Mus musculus
<400> 260
Asp Tyr Asn Met His
1 5
<210> 261
<211> 17
<212> PRT
<213> Mus musculus
<400> 261
Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 262
<211> 14
<212> PRT
<213> Mus musculus
<400> 262
Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
1 5 10
<210> 263
<211> 5
<212> PRT
<213> Mus musculus
<400> 263
Asp Tyr Asn Met His
1 5
<210> 264
<211> 17
<212> PRT
<213> Mus musculus
<400> 264
Glu Ile Asn Pro Asn Ser Gly Gly Ser Gly Tyr Asn Gln Lys Phe Lys
1 5 10 15
Gly
<210> 265
<211> 14
<212> PRT
<213> Mus musculus
<400> 265
Leu Gly Tyr Tyr Gly Asn Tyr Glu Asp Trp Tyr Phe Asp Val
1 5 10
<210> 266
<211> 5
<212> PRT
<213> Mus musculus
<400> 266
Asp Tyr Tyr Ile His
1 5
<210> 267
<211> 17
<212> PRT
<213> Mus musculus
<400> 267
Arg Ile Asp Pro Asp Asn Gly Glu Ser Thr Tyr Val Pro Lys Phe Gln
1 5 10 15
Gly
<210> 268
<211> 13
<212> PRT
<213> Mus musculus
<400> 268
Glu Gly Leu Asp Tyr Gly Asp Tyr Tyr Ala Val Asp Tyr
1 5 10
<210> 269
<211> 5
<212> PRT
<213> Mus musculus
<400> 269
Asp Tyr Ile Met His
1 5
<210> 270
<211> 17
<212> PRT
<213> Mus musculus
<400> 270
Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 271
<211> 11
<212> PRT
<213> Mus musculus
<400> 271
Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr
1 5 10
<210> 272
<211> 5
<212> PRT
<213> Mus musculus
<400> 272
Asp Tyr Tyr Met His
1 5
<210> 273
<211> 17
<212> PRT
<213> Mus musculus
<400> 273
Arg Ile Asp Pro Glu Asn Gly Asp Ile Ile Tyr Asp Pro Lys Phe Gln
1 5 10 15
Gly
<210> 274
<211> 10
<212> PRT
<213> Mus musculus
<400> 274
Asp Ala Gly Asp Pro Ala Trp Phe Thr Tyr
1 5 10
<210> 275
<211> 10
<212> PRT
<213> Mus musculus
<400> 275
Arg Ala Ser Ser Ser Val Tyr Tyr Met His
1 5 10
<210> 276
<211> 7
<212> PRT
<213> Mus musculus
<400> 276
Ala Thr Ser Asn Leu Ala Ser
1 5
<210> 277
<211> 9
<212> PRT
<213> Mus musculus
<400> 277
Gln Gln Trp Ser Ser Asp Pro Leu Thr
1 5
<210> 278
<211> 12
<212> PRT
<213> Mus musculus
<400> 278
Ser Val Ser Ser Thr Ile Ser Ser Asn His Leu His
1 5 10
<210> 279
<211> 7
<212> PRT
<213> Mus musculus
<400> 279
Gly Thr Ser Asn Leu Ala Ser
1 5
<210> 280
<211> 9
<212> PRT
<213> Mus musculus
<400> 280
Gln Gln Trp Ser Ser Tyr Pro Leu Thr
1 5
<210> 281
<211> 10
<212> PRT
<213> Mus musculus
<400> 281
Arg Ala Ser Ser Ser Ile Ser Tyr Ile His
1 5 10
<210> 282
<211> 7
<212> PRT
<213> Mus musculus
<400> 282
Ala Thr Ser Asn Leu Ala Ser
1 5
<210> 283
<211> 9
<212> PRT
<213> Mus musculus
<400> 283
Gln Gln Trp Ser Ser Asp Pro Leu Thr
1 5
<210> 284
<211> 12
<212> PRT
<213> Mus musculus
<400> 284
Arg Ala Ser Ser Ser Val Thr Ser Ser Tyr Leu Asn
1 5 10
<210> 285
<211> 7
<212> PRT
<213> Mus musculus
<400> 285
Ser Thr Ser Asn Leu Ala Ser
1 5
<210> 286
<211> 9
<212> PRT
<213> Mus musculus
<400> 286
Gln Gln Tyr Asp Phe Phe Pro Ser Thr
1 5
<210> 287
<211> 5
<212> PRT
<213> Mus musculus
<400> 287
Asp Tyr Phe Ile His
1 5
<210> 288
<211> 17
<212> PRT
<213> Mus musculus
<400> 288
Arg Leu Asp Pro Glu Asp Gly Glu Ser Asp Tyr Ala Pro Lys Phe Gln
1 5 10 15
Asp
<210> 289
<211> 12
<212> PRT
<213> Mus musculus
<400> 289
Glu Asp Tyr Asp Gly Thr Tyr Thr Phe Phe Pro Tyr
1 5 10
<210> 290
<211> 5
<212> PRT
<213> Mus musculus
<400> 290
Asp Phe Tyr Leu His
1 5
<210> 291
<211> 17
<212> PRT
<213> Mus musculus
<400> 291
Arg Ile Asp Pro Glu Asn Gly Asp Thr Leu Tyr Asp Pro Lys Phe Gln
1 5 10 15
Asp
<210> 292
<211> 16
<212> PRT
<213> Mus musculus
<400> 292
Glu Ala Asp Tyr Phe His Asp Gly Thr Ser Tyr Trp Tyr Phe Asp Val
1 5 10 15
<210> 293
<211> 5
<212> PRT
<213> Mus musculus
<400> 293
Asp Tyr Tyr Ile His
1 5
<210> 294
<211> 17
<212> PRT
<213> Mus musculus
<400> 294
Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala Pro Lys Phe Pro
1 5 10 15
Gly
<210> 295
<211> 12
<212> PRT
<213> Mus musculus
<400> 295
Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro Tyr
1 5 10
<210> 296
<211> 5
<212> PRT
<213> Mus musculus
<400> 296
Asp Tyr Tyr Met Asn
1 5
<210> 297
<211> 17
<212> PRT
<213> Mus musculus
<400> 297
Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn His Lys Phe Lys
1 5 10 15
Gly
<210> 298
<211> 11
<212> PRT
<213> Mus musculus
<400> 298
Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp
1 5 10
<210> 299
<211> 130
<212> PRT
<213> Mus musculus
<400> 299
Met Asp Phe Gln Val Gln Ile Phe Ser Phe Met Leu Ile Ser Val Thr
1 5 10 15
Val Ile Leu Ser Ser Gly Glu Ile Val Leu Thr Gln Ser Pro Ala Leu
20 25 30
Met Ala Ala Ser Pro Gly Glu Lys Val Thr Ile Thr Cys Ser Val Ser
35 40 45
Ser Ser Ile Ser Ser Ser Asn Leu His Trp Ser Gln Gln Lys Ser Gly
50 55 60
Thr Ser Pro Lys Leu Trp Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly
65 70 75 80
Val Pro Val Arg Phe Ser Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu
85 90 95
Thr Ile Ser Ser Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln
100 105 110
Gln Trp Thr Thr Thr Tyr Thr Phe Gly Ser Gly Thr Lys Leu Glu Leu
115 120 125
Lys Arg
130
<210> 300
<211> 390
<212> DNA
<213> Mus musculus
<400> 300
atggattttc aggtgcagat tttcagcttc atgctaatca gtgtcacagt catattgtcc 60
agtggagaaa ttgtgctcac ccagtctcca gcactcatgg ctgcatctcc aggggagaag 120
gtcaccatca cctgcagtgt cagctcgagt ataagttcca gcaacttaca ctggtcccag 180
cagaagtcag gaacctcccc caaactctgg atttatggca catccaacct tgcttctgga 240
gtccctgttc gcttcagtgg cagtggatct gggacctctt attctctcac aatcagcagc 300
atggaggctg aagatgctgc cacttattac tgtcaacagt ggactactac gtatacgttc 360
ggatcgggga ccaagctgga gctgaaacgt 390
<210> 301
<211> 141
<212> PRT
<213> Mus musculus
<400> 301
Met Gly Trp Asn Trp Ile Ile Phe Phe Leu Met Ala Val Val Thr Gly
1 5 10 15
Val Asn Ser Glu Val Gln Leu Arg Gln Ser Gly Ala Asp Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile
35 40 45
Lys Asp Tyr Tyr Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu
50 55 60
Glu Trp Ile Gly Arg Ile Asp Pro Asp Asn Gly Glu Ser Thr Tyr Val
65 70 75 80
Pro Lys Phe Gln Gly Lys Ala Thr Ile Thr Ala Asp Thr Ser Ser Asn
85 90 95
Thr Ala Tyr Leu Gln Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Ile
100 105 110
Tyr Tyr Cys Gly Arg Glu Gly Leu Asp Tyr Gly Asp Tyr Tyr Ala Val
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser
130 135 140
<210> 302
<211> 423
<212> DNA
<213> Mus musculus
<400> 302
atgggatgga actggatcat cttcttcctg atggcagtgg ttacaggggt caattcagag 60
gtgcagttgc ggcagtctgg ggcagacctt gtgaagccag gggcctcagt caagttgtcc 120
tgcacagctt ctggcttcaa cattaaagac tactatatac actgggtgaa gcagaggcct 180
gaacagggcc tggagtggat tggaaggatt gatcctgata atggtgaaag tacatatgtc 240
ccgaagttcc agggcaaggc cactataaca gcagacacat catccaacac agcctaccta 300
caactcagaa gcctgacatc tgaggacact gccatctatt attgtgggag agaggggctc 360
gactatggtg actactatgc tgtggactac tggggtcaag gaacctcggt cacagtctcg 420
agc 423
<210> 303
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 303
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Pro Gly Ala Arg Cys Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Val Ser
35 40 45
Ser Ser Ile Ser Ser Ser Asn Leu His Trp Tyr Gln Gln Lys Pro Gly
50 55 60
Lys Ala Pro Lys Leu Leu Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly
65 70 75 80
Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu
85 90 95
Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
100 105 110
Gln Trp Thr Thr Thr Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
115 120 125
Lys Arg
130
<210> 304
<211> 390
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 304
atggatatgc gcgtgccggc gcagctgctg ggcctgctgc tgctgtggct gccgggcgcg 60
cgctgcgata ttcagctgac ccagagcccg agctttctga gcgcgagcgt gggcgatcgc 120
gtgaccatta cctgcagcgt gagcagcagc attagcagca gcaacctgca ttggtatcag 180
cagaaaccgg gcaaagcgcc gaaactgctg atttatggca ccagcaacct ggcgagcggc 240
gtgccgagcc gctttagcgg cagcggcagc ggcaccgaat ttaccctgac cattagcagc 300
ctgcagccgg aagattttgc gacctattat tgccagcagt ggaccaccac ctataccttt 360
ggccagggca ccaaactgga aattaaacgt 390
<210> 305
<211> 141
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 305
Met Asp Trp Thr Trp Ser Ile Leu Phe Leu Val Ala Ala Pro Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile
35 40 45
Lys Asp Tyr Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Arg Ile Asp Pro Asp Asn Gly Glu Ser Thr Tyr Val
65 70 75 80
Pro Lys Phe Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Glu Gly Leu Asp Tyr Gly Asp Tyr Tyr Ala Val
115 120 125
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135 140
<210> 306
<211> 423
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 306
atggattgga cctggagcat tctgtttctg gtggcggcgc cgaccggcgc gcatagcgaa 60
gtgcagctgg tgcagagcgg cgcggaagtg aaaaaaccgg gcgcgagcgt gaaagtgagc 120
tgcaaagcga gcggctttaa cattaaagat tattatattc attgggtgcg ccaggcgccg 180
ggccagggcc tggaatggat gggccgcatt gatccggata acggcgaaag cacctatgtg 240
ccgaaatttc agggccgcgt gaccatgacc accgatacca gcaccagcac cgcgtatatg 300
gaactgcgca gcctgcgcag cgatgatacc gcggtgtatt attgcgcgcg cgaaggcctg 360
gattatggcg attattatgc ggtggattat tggggccagg gcaccctggt gaccgtctcg 420
agc 423
<210> 307
<211> 127
<212> PRT
<213> Mus musculus
<400> 307
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser
20 25 30
Ala Ser Leu Gly Asp Arg Val Asn Ile Ser Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val
50 55 60
Lys Leu Leu Ile Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser
85 90 95
Asn Leu Ala Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Ile
100 105 110
Lys His Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg
115 120 125
<210> 308
<211> 381
<212> DNA
<213> Mus musculus
<400> 308
atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt 60
gatatccaga tgacacagac tacatcctcc ctgtctgcct ctctgggaga cagagtcaac 120
atcagctgca gggcaagtca ggacattagc agttatttaa actggtatca gcagaaacca 180
gatggaactg ttaaactcct gatctactcc acatcaagat taaactcagg agtcccatca 240
aggttcagtg gcagtgggtc tgggacagat tattctctca ctattagcaa cctggcacaa 300
gaagatattg ccacttactt ttgccaacag gatattaagc atccgacgtt cggtggaggc 360
accaagttgg agctgaaacg t 381
<210> 309
<211> 139
<212> PRT
<213> Mus musculus
<400> 309
Met Glu Trp Ile Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys
20 25 30
Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr Ile Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met Asp Leu Ser Ser Leu Thr Ser Glu Gly Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135
<210> 310
<211> 417
<212> DNA
<213> Mus musculus
<400> 310
atggaatgga tctggatatt tctcttcctc ctgtcaggaa ctgcaggtgt ccactctgag 60
gtccagctgc agcagtctgg acctgagctg gtaaagcctg gggcttcagt gaagatgtcc 120
tgcaaggctt ctgggttcac attcactgac tacattatgc actgggtgaa gcagaagcct 180
gggcagggcc ttgagtggat tggatatatt aatccttaca atgatgatac tgaatacaat 240
gagaagttca aaggcaaggc cacactgact tcagacaaat cctccagcac agcctacatg 300
gatctcagca gtctgacctc tgagggctct gcggtctatt actgtgcaag atcgatttat 360
tactacgatg ccccgtttgc ttactggggc caagggactc tggtcacagt ctcgagc 417
<210> 311
<211> 127
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 311
Met Met Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln
1 5 10 15
Gly Thr Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp
35 40 45
Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
50 55 60
Lys Leu Leu Ile Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val Pro Ser
65 70 75 80
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Ile
100 105 110
Lys His Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
115 120 125
<210> 312
<211> 381
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 312
atgatgtcct ctgctcagtt ccttggtctc ctgttgctct gttttcaagg taccagatgt 60
gatatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggtga ccgtgtcacc 120
atcacttgcc gcgcaagtca ggatattagc agctatttaa attggtatca gcagaaacca 180
gggaaagccc ctaagctcct gatctattct acttcccgtt tgaatagtgg ggtcccatca 240
cgcttcagtg gcagtggctc tgggacagat ttcactctca ccatcagcag tctgcaacct 300
gaagattttg caacttacta ctgtcaacag gatattaaac accctacgtt cggtcaaggc 360
accaaggtgg agatcaaacg t 381
<210> 313
<211> 139
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 313
Met Glu Trp Ile Trp Ile Phe Leu Phe Leu Leu Ser Gly Thr Ala Gly
1 5 10 15
Val His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135
<210> 314
<211> 107
<212> PRT
<213> Mus musculus
<400> 314
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Asn Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Ala Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Ile Lys His Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg
100 105
<210> 315
<211> 128
<212> PRT
<213> Mus musculus
<400> 315
Met Lys Ser Gln Thr Gln Val Phe Val Tyr Met Leu Leu Trp Leu Ser
1 5 10 15
Gly Val Glu Gly Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser
20 25 30
Thr Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp
35 40 45
Val Phe Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro
50 55 60
Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp
65 70 75 80
Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
85 90 95
Asn Val Gln Ser Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser
100 105 110
Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg
115 120 125
<210> 316
<211> 381
<212> DNA
<213> Mus musculus
<400> 316
atgaagtcac agacccaggt ctttgtatac atgttgctgt ggttgtctgg tgttgaagga 60
gacattgtga tgacccagtc tcacaaattc atgtccacgt cagtaggaga cagggtcacc 120
atcacctgca aggccagtca ggatgtcttt actgctgtag cctggtatca acagaaacca 180
ggacaatctc ctaaactact gatttactgg gcatccaccc ggcacactgg agtccctgat 240
cgcttcacag gcagtggatc tgggacagat ttcactctca ccattagcaa tgtgcagtct 300
gaagacttgg cagattattt ctgtcaacaa tatagcagct atcctctcac gttcggtgct 360
gggaccaagt tggagctgaa a 381
<210> 317
<211> 138
<212> PRT
<213> Mus musculus
<400> 317
Met Gly Trp Asn Trp Ile Ile Phe Phe Leu Met Ala Val Val Thr Gly
1 5 10 15
Val Asn Ser Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg
20 25 30
Pro Gly Ala Leu Val Lys Leu Ser Cys Lys Ala Ser Gly Phe Asn Ile
35 40 45
Lys Asp Tyr Tyr Met His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu
50 55 60
Glu Trp Ile Gly Arg Ile Asp Pro Glu Asn Gly Asp Ile Ile Tyr Asp
65 70 75 80
Pro Lys Phe Gln Gly Lys Ala Ser Ile Thr Thr Asp Thr Ser Ser Asn
85 90 95
Thr Ala Tyr Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Tyr Asp Ala Gly Asp Pro Ala Trp Phe Thr Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135
<210> 318
<211> 411
<212> DNA
<213> Mus musculus
<400> 318
atgggatgga actggatcat cttcttcctg atggcagtgg ttacaggggt caattcagag 60
gttcagctgc agcagtctgg ggctgagctt gtgaggccag gggccttagt caagttgtcc 120
tgcaaagctt ctggcttcaa tattaaagac tactatatgc actgggtgaa gcagaggcct 180
gaacagggcc tggagtggat tggaaggatt gatcctgaga atggtgatat tatatatgac 240
ccgaagttcc agggcaaggc cagtataaca acagacacat cctccaacac agcctacctg 300
cagctcagca gcctgacgtc tgaggacact gccgtctatt actgtgctta cgatgctggt 360
gaccccgcct ggtttactta ctggggccaa gggactctgg tcaccgtctc g 411
<210> 319
<211> 130
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 319
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
35 40 45
Gln Asp Val Phe Thr Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg His Thr Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Tyr Ser Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
115 120 125
Lys Arg
130
<210> 320
<211> 390
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 320
atggatatgc gcgtgccggc gcagctgctg ggcctgctgc tgctgtggct gcgcggcgcg 60
cgctgcgata tccagatgac ccagagcccg agcagcctga gcgcgagcgt gggcgatcgc 120
gtgaccatta cctgcaaagc gagccaggat gtgtttaccg cggtggcgtg gtatcagcag 180
aaaccgggca aagcgccgaa actgctgatt tattgggcga gcacccgcca taccggcgtg 240
ccgagtcgct ttagcggcag cggcagcggc accgatttta ccctgaccat tagcagcctg 300
cagccggaag attttgcgac ctattattgc cagcagtata gcagctatcc gctgaccttt 360
ggcggcggca ccaaagtgga aattaaacgt 390
<210> 321
<211> 138
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 321
Met Asp Trp Thr Trp Ser Ile Leu Phe Leu Val Ala Ala Pro Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile
35 40 45
Lys Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Arg Ile Asp Pro Glu Asn Gly Asp Ile Ile Tyr Asp
65 70 75 80
Pro Lys Phe Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Tyr Asp Ala Gly Asp Pro Ala Trp Phe Thr Tyr Trp
115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
130 135
<210> 322
<211> 414
<212> DNA
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 322
atggattgga cctggagcat tctgtttctg gtggcggcgc cgaccggcgc gcatagcgaa 60
gtgcagctgg tgcagagcgg cgcggaagtg aaaaaaccgg gcgcgagcgt gaaagtgagc 120
tgcaaagcga gcggctttaa cattaaagat tattatatgc attgggtgcg ccaggcgccg 180
ggccagggcc tggaatggat cggccgcatt gatccggaaa acggcgatat tatttatgat 240
ccgaaatttc agggccgcgt gaccatgacc accgatacca gcaccagcac cgcgtatatg 300
gaactgcgca gcctgcgcag cgatgatacc gcggtgtatt attgcgcgta tgatgcgggc 360
gatccggcgt ggtttaccta ttggggccag ggcaccctgg tgaccgtctc gagc 414
<210> 323
<211> 106
<212> PRT
<213> Mus musculus
<400> 323
Thr Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
1 5 10 15
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
20 25 30
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
35 40 45
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
50 55 60
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
65 70 75 80
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
85 90 95
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
100 105
<210> 324
<211> 324
<212> PRT
<213> Mus musculus
<400> 324
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
1 5 10 15
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
100 105 110
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
115 120 125
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
130 135 140
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
145 150 155 160
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
165 170 175
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
180 185 190
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
195 200 205
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
210 215 220
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
225 230 235 240
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
245 250 255
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
260 265 270
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys Leu Asn
275 280 285
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
290 295 300
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
305 310 315 320
Ser Pro Gly Lys
<210> 325
<211> 106
<212> PRT
<213> 智人
<400> 325
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln
1 5 10 15
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr
20 25 30
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser
35 40 45
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr
50 55 60
Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
65 70 75 80
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
85 90 95
Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
100 105
<210> 326
<211> 327
<212> PRT
<213> 智人
<400> 326
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg
1 5 10 15
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
50 55 60
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
65 70 75 80
Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
85 90 95
Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro
100 105 110
Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys
115 120 125
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val
130 135 140
Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
145 150 155 160
Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe
165 170 175
Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp
180 185 190
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
195 200 205
Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg
210 215 220
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys
225 230 235 240
Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp
245 250 255
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys
260 265 270
Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser
275 280 285
Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser
290 295 300
Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser
305 310 315 320
Leu Ser Leu Ser Leu Gly Lys
325
<210> 327
<211> 120
<212> PRT
<213> Mus musculus
<400> 327
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Ile Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Thr Ser Glu Gly Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 328
<211> 120
<212> PRT
<213> Mus musculus
<400> 328
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Ile Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Thr Ser Glu Gly Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 329
<211> 120
<212> PRT
<213> Mus musculus
<400> 329
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 330
<211> 226
<212> PRT
<213> Mus musculus
<400> 330
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Ile Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Thr Ser Glu Gly Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Thr Val Ala Ala Pro Ser Val Phe
115 120 125
Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val
130 135 140
Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp
145 150 155 160
Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
165 170 175
Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
180 185 190
Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
195 200 205
Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
210 215 220
Glu Cys
225
<210> 331
<211> 447
<212> PRT
<213> Mus musculus
<400> 331
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro
210 215 220
Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser
290 295 300
Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile
325 330 335
Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys
435 440 445
<210> 332
<211> 107
<212> PRT
<213> Mus musculus
<400> 332
Asp Ile Gln Met Thr Gln Ile Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Ser Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Phe Lys Leu Leu Ile
35 40 45
Phe Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Tyr Asn Leu Glu Gln
65 70 75 80
Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 333
<211> 324
<212> PRT
<213> Mus musculus
<400> 333
Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro Leu Ala Pro Gly Ser Ala
1 5 10 15
Ala Gln Thr Asn Ser Met Val Thr Leu Gly Cys Leu Val Lys Gly Tyr
20 25 30
Phe Pro Glu Pro Val Thr Val Thr Trp Asn Ser Gly Ser Leu Ser Ser
35 40 45
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu
50 55 60
Ser Ser Ser Val Thr Val Pro Ser Ser Thr Trp Pro Ser Glu Thr Val
65 70 75 80
Thr Cys Asn Val Ala His Pro Ala Ser Ser Thr Lys Val Asp Lys Lys
85 90 95
Ile Val Pro Arg Asp Cys Gly Cys Lys Pro Cys Ile Cys Thr Val Pro
100 105 110
Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp Val Leu
115 120 125
Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp Ile Ser
130 135 140
Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp Val Glu
145 150 155 160
Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn Ser Thr
165 170 175
Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp Leu Asn
180 185 190
Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro Ala Pro
195 200 205
Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala Pro Gln
210 215 220
Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp Lys Val
225 230 235 240
Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile Thr Val
245 250 255
Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn Thr Gln
260 265 270
Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Ile Tyr Ser Lys Leu Asn
275 280 285
Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys Ser Val
290 295 300
Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu Ser His
305 310 315 320
Ser Pro Gly Lys
<210> 334
<211> 213
<212> PRT
<213> Mus musculus
<400> 334
Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly
1 5 10 15
Asp Arg Val Asn Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile
35 40 45
Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Ala Gln
65 70 75 80
Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Ile Lys His Pro Thr
85 90 95
Phe Gly Gly Gly Thr Lys Leu Glu Leu Lys Arg Thr Asp Ala Ala Pro
100 105 110
Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln Leu Thr Ser Gly Gly
115 120 125
Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr Pro Lys Asp Ile Asn
130 135 140
Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln Asn Gly Val Leu Asn
145 150 155 160
Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr Tyr Ser Met Ser Ser
165 170 175
Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg His Asn Ser Tyr Thr
180 185 190
Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro Ile Val Lys Ser Phe
195 200 205
Asn Arg Asn Glu Cys
210
<210> 335
<211> 444
<212> PRT
<213> Mus musculus
<400> 335
Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Met Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Ile Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met Asp Leu Ser Ser Leu Thr Ser Glu Gly Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val
115 120 125
Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr
130 135 140
Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr
145 150 155 160
Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser
180 185 190
Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala
195 200 205
Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys
210 215 220
Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe
225 230 235 240
Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val
245 250 255
Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe
260 265 270
Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro
275 280 285
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro
290 295 300
Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val
305 310 315 320
Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr
325 330 335
Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys
340 345 350
Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp
355 360 365
Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro
370 375 380
Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser
385 390 395 400
Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala
405 410 415
Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His
420 425 430
His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440
<210> 336
<211> 108
<212> PRT
<213> Mus musculus
<400> 336
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Phe Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 337
<211> 324
<212> DNA
<213> Mus musculus
<400> 337
gatatccaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgca aagcgagcca ggatgtgttt accgcggtgg cgtggtatca gcagaaaccg 120
ggcaaagcgc cgaaactgct gatttattgg gcgagcaccc gccataccgg cgtgccgagt 180
cgctttagcg gcagcggcag cggcaccgat tttaccctga ccattagcag cctgcagccg 240
gaagattttg cgacctatta ttgccagcag tatagcagct atccgctgac ctttggcggc 300
ggcaccaaag tggaaattaa acgt 324
<210> 338
<211> 119
<212> PRT
<213> Mus musculus
<400> 338
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asn Gly Asp Ile Ile Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Tyr Asp Ala Gly Asp Pro Ala Trp Phe Thr Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 339
<211> 357
<212> DNA
<213> Mus musculus
<400> 339
gaagtgcagc tggtgcagag cggcgcggaa gtgaaaaaac cgggcgcgag cgtgaaagtg 60
agctgcaaag cgagcggctt taacattaaa gattattata tgcattgggt gcgccaggcg 120
ccgggccagg gcctggaatg gatcggccgc attgatccgg aaaacggcga tattatttat 180
gatccgaaat ttcagggccg cgtgaccatg accaccgata ccagcaccag caccgcgtat 240
atggaactgc gcagcctgcg cagcgatgat accgcggtgt attattgcgc gtatgatgcg 300
ggcgatccgg cgtggtttac ctattggggc cagggcaccc tggtgaccgt ctcgagc 357
<210> 340
<211> 1395
<212> DNA
<213> Mus musculus
<400> 340
atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactccgag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg ggtcctcggt gaaggtctcc 120
tgcaaggctt ctggttttac cttcaccgac tatattatgc actgggtgcg tcaggcccct 180
ggtcaagggc ttgagtggat gggctatatc aacccttata atgatgacac cgaatacaac 240
gagaagttca agggccgtgt cacgattacc gcggacaaat ccacgagcac agcctacatg 300
gagctgagca gcctgcgctc tgaggacacg gccgtgtatt actgtgcgcg ttcgatttat 360
tactacgatg ccccgtttgc ttactggggc caagggactc tggtcaccgt ctctagtgcc 420
tccaccaagg gcccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 660
acctgcaacg tagatcacaa gcccagcaac accaaggtgg acaagacagt tgagcgcaaa 720
tgttgtgtcg agtgcccacc gtgcccagca ccacctgtgg caggaccgtc agtcttcctc 780
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacgtgcgtg 840
gtggtggacg tgagccacga agaccccgag gtccagttca actggtacgt ggacggcgtg 900
gaggtgcata atgccaagac aaagccacgg gaggagcagt tcaacagcac gttccgtgtg 960
gtcagcgtcc tcaccgttgt gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020
gtctccaaca aaggcctccc agcccccatc gagaaaacca tctccaaaac caaagggcag 1080
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1200
agcaatgggc agccggagaa caactacaag accacacctc ccatgctgga ctccgacggc 1260
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380
ctgtctccgg gtaaa 1395
<210> 341
<211> 213
<212> PRT
<213> Mus musculus
<400> 341
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Ile Lys His Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro
100 105 110
Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr
115 120 125
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys
130 135 140
Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu
145 150 155 160
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser
165 170 175
Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala
180 185 190
Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe
195 200 205
Asn Arg Gly Glu Cys
210
<210> 342
<211> 639
<212> DNA
<213> Mus musculus
<400> 342
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggtga ccgtgtcacc 60
atcacttgcc gcgcaagtca ggatattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctattct acttcccgtt tgaatagtgg ggtcccatca 180
cgcttcagtg gcagtggctc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag gatattaaac accctacgtt cggtcaaggc 300
accaaggtgg agatcaaacg tacggtggct gcaccatctg tcttcatctt cccgccatct 360
gatgagcagt tgaaatctgg aactgcctct gttgtgtgcc tgctgaataa cttctatccc 420
agagaggcca aagtacagtg gaaggtggat aacgccctcc aatcgggtaa ctcccaggag 480
agtgtcacag agcaggacag caaggacagc acctacagcc tcagcagcac cctgacgctg 540
agcaaagcag actacgagaa acacaaagtc tacgcctgcg aagtcaccca tcagggcctg 600
agctcgcccg tcacaaagag cttcaacagg ggagagtgt 639
<210> 343
<211> 235
<212> PRT
<213> Mus musculus
<400> 343
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
35 40 45
Gln Asp Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys
50 55 60
Ala Pro Lys Leu Leu Ile Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val
65 70 75 80
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
85 90 95
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
100 105 110
Asp Ile Lys His Pro Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
130 135 140
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
145 150 155 160
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
165 170 175
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
180 185 190
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
210 215 220
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235
<210> 344
<211> 705
<212> DNA
<213> Mus musculus
<400> 344
atggacatga gggtgcccgc tcagctcctg gggctcctgc tgctgtggct gagaggtgcc 60
agatgtgaca tccagatgac ccagtctcca tcctccctgt ctgcatctgt aggtgaccgt 120
gtcaccatca cttgccgcgc aagtcaggat attagcagct atttaaattg gtatcagcag 180
aaaccaggga aagcccctaa gctcctgatc tattctactt cccgtttgaa tagtggggtc 240
ccatcacgct tcagtggcag tggctctggg acagatttca ctctcaccat cagcagtctg 300
caacctgaag attttgcaac ttactactgt caacaggata ttaaacaccc tacgttcggt 360
caaggcacca aggtggagat caaacgtacg gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg 600
acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt cacccatcag 660
ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt 705
<210> 345
<211> 446
<212> PRT
<213> Mus musculus
<400> 345
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
210 215 220
Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
290 295 300
Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 346
<211> 1338
<212> DNA
<213> Mus musculus
<400> 346
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggttt taccttcacc gactatatta tgcactgggt gcgtcaggcc 120
cctggtcaag ggcttgagtg gatgggctat atcaaccctt ataatgatga caccgaatac 180
aacgagaagt tcaagggccg tgtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgcg ctctgaggac acggccgtgt attactgtgc gcgttcgatt 300
tattactacg atgccccgtt tgcttactgg ggccaaggga ctctggtcac cgtctctagt 360
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 420
agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 480
tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 540
ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 600
tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 660
aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 720
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 780
gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 840
gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 900
gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 960
aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1020
cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1080
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1140
gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1200
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 1260
gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 1320
tccctgtctc cgggtaaa 1338
<210> 347
<211> 465
<212> PRT
<213> Mus musculus
<400> 347
Met Asp Trp Thr Trp Arg Ile Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15
Ala His Ser Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
20 25 30
Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe
35 40 45
Thr Asp Tyr Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
50 55 60
Glu Trp Met Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn
65 70 75 80
Glu Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
85 90 95
Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr
115 120 125
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
130 135 140
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
145 150 155 160
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
165 170 175
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
180 185 190
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
195 200 205
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
210 215 220
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
225 230 235 240
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
245 250 255
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
260 265 270
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
275 280 285
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
290 295 300
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
305 310 315 320
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
325 330 335
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
340 345 350
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
355 360 365
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
370 375 380
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
385 390 395 400
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
405 410 415
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
420 425 430
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
435 440 445
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
450 455 460
Lys
465
<210> 348
<211> 1395
<212> DNA
<213> Mus musculus
<400> 348
atggactgga cctggaggat cctcttcttg gtggcagcag ccacaggagc ccactccgag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg ggtcctcggt gaaggtctcc 120
tgcaaggctt ctggttttac cttcaccgac tatattatgc actgggtgcg tcaggcccct 180
ggtcaagggc ttgagtggat gggctatatc aacccttata atgatgacac cgaatacaac 240
gagaagttca agggccgtgt cacgattacc gcggacaaat ccacgagcac agcctacatg 300
gagctgagca gcctgcgctc tgaggacacg gccgtgtatt actgtgcgcg ttcgatttat 360
tactacgatg ccccgtttgc ttactggggc caagggactc tggtcaccgt ctctagtgcc 420
tccaccaagg gcccatcggt cttccccctg gcgccctgct ccaggagcac ctccgagagc 480
acagcggccc tgggctgcct ggtcaaggac tacttccccg aaccggtgac ggtgtcgtgg 540
aactcaggcg ctctgaccag cggcgtgcac accttcccag ctgtcctaca gtcctcagga 600
ctctactccc tcagcagcgt ggtgaccgtg ccctccagca acttcggcac ccagacctac 660
acctgcaacg tagatcacaa gcccagcaac accaaggtgg acaagacagt tgagcgcaaa 720
tgttgtgtcg agtgcccacc gtgcccagca ccacctgtgg caggaccgtc agtcttcctc 780
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacgtgcgtg 840
gtggtggacg tgagccacga agaccccgag gtccagttca actggtacgt ggacggcgtg 900
gaggtgcata atgccaagac aaagccacgg gaggagcagt tcaacagcac gttccgtgtg 960
gtcagcgtcc tcaccgttgt gcaccaggac tggctgaacg gcaaggagta caagtgcaag 1020
gtctccaaca aaggcctccc agcccccatc gagaaaacca tctccaaaac caaagggcag 1080
ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac caagaaccag 1140
gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt ggagtgggag 1200
agcaatgggc agccggagaa caactacaag accacacctc ccatgctgga ctccgacggc 1260
tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1320
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1380
ctgtctccgg gtaaa 1395
<210> 349
<211> 417
<212> DNA
<213> Mus musculus
<400> 349
atggaatgga tctggatatt tctcttcctc ctgtcaggaa ctgcaggtgt ccactctgag 60
gtgcagctgg tgcagtctgg ggctgaggtg aagaagcctg ggtcctcggt gaaggtctcc 120
tgcaaggctt ctggttttac cttcaccgac tatattatgc actgggtgcg tcaggcccct 180
ggtcaagggc ttgagtggat gggctatatc aacccttata atgatgacac cgaatacaac 240
gagaagttca agggccgtgt cacgattacc gcggacaaat ccacgagcac agcctacatg 300
gagctgagca gcctgcgctc tgaggacacg gccgtgtatt actgtgcgcg ttcgatttat 360
tactacgatg ccccgtttgc ttactggggc caagggactc tggtcacagt ctcgagc 417
<210> 350
<211> 218
<212> PRT
<213> Mus musculus
<400> 350
Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Gln Arg Ala Thr Ile Ala Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp
20 25 30
Gly Thr Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Glu Ile Pro Ala
50 55 60
Arg Phe Ser Gly Thr Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His
65 70 75 80
Pro Val Glu Glu Glu Asp Ile Thr Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
100 105 110
Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu Gln
115 120 125
Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe Tyr
130 135 140
Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg Gln
145 150 155 160
Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser Thr
165 170 175
Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu Arg
180 185 190
His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser Pro
195 200 205
Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
210 215
<210> 351
<211> 15
<212> PRT
<213> Mus musculus
<400> 351
Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Thr Ser Tyr Met Asn
1 5 10 15
<210> 352
<211> 7
<212> PRT
<213> Mus musculus
<400> 352
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 353
<211> 9
<212> PRT
<213> Mus musculus
<400> 353
Gln Gln Ser Asn Glu Asp Pro Phe Thr
1 5
<210> 354
<211> 657
<212> DNA
<213> Mus musculus
<400> 354
gacattgtgt tgacccagtc tccagcttct ttggctgtgt ctctagggca gagggccacc 60
atcgcctgca aggccagcca aagtgttgat tatgatggta ctagttatat gaattggtac 120
caacagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa tctagaatct 180
gagatcccag ccaggtttag tggcactggg tctgggacag acttcaccct caacatccat 240
cctgtggagg aggaggatat cacaacctat tactgtcagc aaagtaatga ggatccgttc 300
acgttcggag gggggaccaa gttggaaata aaacgggctg atgctgcacc aactgtatcc 360
atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 420
aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 480
aatggcgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 540
agcaccctca cgttgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 600
actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgttag 657
<210> 355
<211> 238
<212> PRT
<213> Mus musculus
<400> 355
Met Glu Thr Asp Thr Ile Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
20 25 30
Val Ser Leu Gly Gln Arg Ala Thr Ile Ala Cys Lys Ala Ser Gln Ser
35 40 45
Val Asp Tyr Asp Gly Thr Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
50 55 60
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser
65 70 75 80
Glu Ile Pro Ala Arg Phe Ser Gly Thr Gly Ser Gly Thr Asp Phe Thr
85 90 95
Leu Asn Ile His Pro Val Glu Glu Glu Asp Ile Thr Thr Tyr Tyr Cys
100 105 110
Gln Gln Ser Asn Glu Asp Pro Phe Thr Phe Gly Gly Gly Thr Lys Leu
115 120 125
Glu Ile Lys Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro
130 135 140
Ser Ser Glu Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu
145 150 155 160
Asn Asn Phe Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly
165 170 175
Ser Glu Arg Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser
180 185 190
Lys Asp Ser Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp
195 200 205
Glu Tyr Glu Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr
210 215 220
Ser Thr Ser Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys
225 230 235
<210> 356
<211> 717
<212> DNA
<213> Mus musculus
<400> 356
atggagacag acacaatcct gctatgggtg ctgctgctct gggttccagg ctccactggt 60
gacattgtgt tgacccagtc tccagcttct ttggctgtgt ctctagggca gagggccacc 120
atcgcctgca aggccagcca aagtgttgat tatgatggta ctagttatat gaattggtac 180
caacagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa tctagaatct 240
gagatcccag ccaggtttag tggcactggg tctgggacag acttcaccct caacatccat 300
cctgtggagg aggaggatat cacaacctat tactgtcagc aaagtaatga ggatccgttc 360
acgttcggag gggggaccaa gttggaaata aaacgggctg atgctgcacc aactgtatcc 420
atcttcccac catccagtga gcagttaaca tctggaggtg cctcagtcgt gtgcttcttg 480
aacaacttct accccaaaga catcaatgtc aagtggaaga ttgatggcag tgaacgacaa 540
aatggcgtcc tgaacagttg gactgatcag gacagcaaag acagcaccta cagcatgagc 600
agcaccctca cgttgaccaa ggacgagtat gaacgacata acagctatac ctgtgaggcc 660
actcacaaga catcaacttc acccattgtc aagagcttca acaggaatga gtgttag 717
<210> 357
<211> 442
<212> PRT
<213> Mus musculus
<400> 357
Gln Val Gln Leu Gln Gln Pro Gly Thr Glu Leu Val Arg Pro Gly Thr
1 5 10 15
Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Thr Tyr
20 25 30
Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Ser Ala Ser Glu Ile Arg Leu Asp Gln Lys Phe
50 55 60
Lys Asp Lys Ala Thr Leu Thr Leu Asp Lys Ser Ser Ser Thr Ala Tyr
65 70 75 80
Met His Leu Ser Gly Pro Thr Ser Val Asp Ser Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Gly Glu Trp Gly Ser Met Asp Tyr Trp Gly Gln Gly Thr
100 105 110
Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser Val Tyr Pro
115 120 125
Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val Thr Leu Gly
130 135 140
Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val Thr Trp Asn
145 150 155 160
Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro Ser Ser Thr
180 185 190
Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro Ala Ser Ser
195 200 205
Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly Cys Lys Pro
210 215 220
Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro
225 230 235 240
Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys
245 250 255
Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp
260 265 270
Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu
275 280 285
Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met
290 295 300
His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser
305 310 315 320
Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly
325 330 335
Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln
340 345 350
Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe
355 360 365
Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu
370 375 380
Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe
385 390 395 400
Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn
405 410 415
Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His His Thr
420 425 430
Glu Lys Ser Leu Ser His Ser Pro Gly Lys
435 440
<210> 358
<211> 5
<212> PRT
<213> Mus musculus
<400> 358
Thr Tyr Trp Met Asn
1 5
<210> 359
<211> 17
<212> PRT
<213> Mus musculus
<400> 359
Met Ile His Pro Ser Ala Ser Glu Ile Arg Leu Asp Gln Lys Phe Lys
1 5 10 15
Asp
<210> 360
<211> 9
<212> PRT
<213> Mus musculus
<400> 360
Ser Gly Glu Trp Gly Ser Met Asp Tyr
1 5
<210> 361
<211> 1329
<212> DNA
<213> Mus musculus
<400> 361
caggtccaac tacagcagcc tgggactgag ctggtgaggc ctggaacttc agtgaagttg 60
tcctgtaagg cttctggcta catcttcacc acctactgga tgaactgggt gaaacagagg 120
cctggacaag gccttgagtg gattggcatg attcatcctt ccgcaagtga aattaggttg 180
gatcagaaat tcaaggacaa ggccacattg actcttgaca aatcctccag cacagcctat 240
atgcacctca gcggcccgac atctgtggat tctgcggtct attactgtgc aagatcaggg 300
gaatgggggt ctatggacta ctggggtcaa ggaacctcag tcaccgtctc ctcagccaaa 360
acgacacccc catctgtcta tccactggcc cctggatctg ctgcccaaac taactccatg 420
gtgaccctgg gatgcctggt caagggctat ttccctgagc cagtgacagt gacctggaac 480
tctggatccc tgtccagcgg tgtgcacacc ttcccagctg tcctgcagtc tgacctctac 540
actctgagca gctcagtgac tgtcccctcc agcacctggc ccagcgagac cgtcacctgc 600
aacgttgccc acccggccag cagcaccaag gtggacaaga aaattgtgcc cagggattgt 660
ggttgtaagc cttgcatatg tacagtccca gaagtatcat ctgtcttcat cttcccccca 720
aagcccaagg atgtgctcac cattactctg actcctaagg tcacgtgtgt tgtggtagac 780
atcagcaagg atgatcccga ggtccagttc agctggtttg tagatgatgt ggaggtgcac 840
acagctcaga cgcaaccccg ggaggagcag ttcaacagca ctttccgctc agtcagtgaa 900
cttcccatca tgcaccagga ctggctcaat ggcaaggagt tcaaatgcag ggtcaacagt 960
gcagctttcc ctgcccccat cgagaaaacc atctccaaaa ccaaaggcag accgaaggct 1020
ccacaggtgt acaccattcc acctcccaag gagcagatgg ccaaggataa agtcagtctg 1080
acctgcatga taacagactt cttccctgaa gacattactg tggagtggca gtggaatggg 1140
cagccagcgg agaactacaa gaacactcag cccatcatgg acacagatgg ctcttacttc 1200
atctacagca agctcaatgt gcagaagagc aactgggagg caggaaatac tttcacctgc 1260
tctgtgttac atgagggcct gcacaaccac catactgaga agagcctctc ccactctcct 1320
ggtaaatga 1329
<210> 362
<211> 461
<212> PRT
<213> Mus musculus
<400> 362
Met Gly Trp Ser Ser Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly
1 5 10 15
Val His Ser Gln Val Gln Leu Gln Gln Pro Gly Thr Glu Leu Val Arg
20 25 30
Pro Gly Thr Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ile Phe
35 40 45
Thr Thr Tyr Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu
50 55 60
Glu Trp Ile Gly Met Ile His Pro Ser Ala Ser Glu Ile Arg Leu Asp
65 70 75 80
Gln Lys Phe Lys Asp Lys Ala Thr Leu Thr Leu Asp Lys Ser Ser Ser
85 90 95
Thr Ala Tyr Met His Leu Ser Gly Pro Thr Ser Val Asp Ser Ala Val
100 105 110
Tyr Tyr Cys Ala Arg Ser Gly Glu Trp Gly Ser Met Asp Tyr Trp Gly
115 120 125
Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro Ser
130 135 140
Val Tyr Pro Leu Ala Pro Gly Ser Ala Ala Gln Thr Asn Ser Met Val
145 150 155 160
Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Val
165 170 175
Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala
180 185 190
Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Pro
195 200 205
Ser Ser Thr Trp Pro Ser Glu Thr Val Thr Cys Asn Val Ala His Pro
210 215 220
Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Val Pro Arg Asp Cys Gly
225 230 235 240
Cys Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile
245 250 255
Phe Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys
260 265 270
Val Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln
275 280 285
Phe Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln
290 295 300
Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu
305 310 315 320
Pro Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg
325 330 335
Val Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
340 345 350
Thr Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro
355 360 365
Lys Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr
370 375 380
Asp Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln
385 390 395 400
Pro Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly
405 410 415
Ser Tyr Phe Ile Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu
420 425 430
Ala Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn
435 440 445
His His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys
450 455 460
<210> 363
<211> 1386
<212> DNA
<213> Mus musculus
<400> 363
atgggatgga gctctatcat cctcttcttg gtagcaacag ctacaggtgt ccactcccag 60
gtccaactac agcagcctgg gactgagctg gtgaggcctg gaacttcagt gaagttgtcc 120
tgtaaggctt ctggctacat cttcaccacc tactggatga actgggtgaa acagaggcct 180
ggacaaggcc ttgagtggat tggcatgatt catccttccg caagtgaaat taggttggat 240
cagaaattca aggacaaggc cacattgact cttgacaaat cctccagcac agcctatatg 300
cacctcagcg gcccgacatc tgtggattct gcggtctatt actgtgcaag atcaggggaa 360
tgggggtcta tggactactg gggtcaagga acctcagtca ccgtctcctc agccaaaacg 420
acacccccat ctgtctatcc actggcccct ggatctgctg cccaaactaa ctccatggtg 480
accctgggat gcctggtcaa gggctatttc cctgagccag tgacagtgac ctggaactct 540
ggatccctgt ccagcggtgt gcacaccttc ccagctgtcc tgcagtctga cctctacact 600
ctgagcagct cagtgactgt cccctccagc acctggccca gcgagaccgt cacctgcaac 660
gttgcccacc cggccagcag caccaaggtg gacaagaaaa ttgtgcccag ggattgtggt 720
tgtaagcctt gcatatgtac agtcccagaa gtatcatctg tcttcatctt ccccccaaag 780
cccaaggatg tgctcaccat tactctgact cctaaggtca cgtgtgttgt ggtagacatc 840
agcaaggatg atcccgaggt ccagttcagc tggtttgtag atgatgtgga ggtgcacaca 900
gctcagacgc aaccccggga ggagcagttc aacagcactt tccgctcagt cagtgaactt 960
cccatcatgc accaggactg gctcaatggc aaggagttca aatgcagggt caacagtgca 1020
gctttccctg cccccatcga gaaaaccatc tccaaaacca aaggcagacc gaaggctcca 1080
caggtgtaca ccattccacc tcccaaggag cagatggcca aggataaagt cagtctgacc 1140
tgcatgataa cagacttctt ccctgaagac attactgtgg agtggcagtg gaatgggcag 1200
ccagcggaga actacaagaa cactcagccc atcatggaca cagatggctc ttacttcatc 1260
tacagcaagc tcaatgtgca gaagagcaac tgggaggcag gaaatacttt cacctgctct 1320
gtgttacatg agggcctgca caaccaccat actgagaaga gcctctccca ctctcctggt 1380
aaatga 1386
<210> 364
<211> 106
<212> PRT
<213> Mus musculus
<400> 364
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Ser Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Ser Thr Ser Arg Leu Asn Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Asp Ile Lys His Pro Thr
85 90 95
Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
<210> 365
<211> 318
<212> DNA
<213> Mus musculus
<400> 365
gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggtga ccgtgtcacc 60
atcacttgcc gcgcaagtca ggatattagc agctatttaa attggtatca gcagaaacca 120
gggaaagccc ctaagctcct gatctattct acttcccgtt tgaatagtgg ggtcccatca 180
cgcttcagtg gcagtggctc tgggacagat ttcactctca ccatcagcag tctgcaacct 240
gaagattttg caacttacta ctgtcaacag gatattaaac accctacgtt cggtcaaggc 300
accaaggtgg agatcaaa 318
<210> 366
<211> 120
<212> PRT
<213> Mus musculus
<400> 366
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 367
<211> 360
<212> DNA
<213> Mus musculus
<400> 367
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc ggtgaaggtc 60
tcctgcaagg cttctggttt taccttcacc gactatatta tgcactgggt gcgtcaggcc 120
cctggtcaag ggcttgagtg gatgggctat atcaaccctt ataatgatga caccgaatac 180
aacgagaagt tcaagggccg tgtcacgatt accgcggaca aatccacgag cacagcctac 240
atggagctga gcagcctgcg ctctgaggac acggccgtgt attactgtgc gcgttcgatt 300
tattactacg atgccccgtt tgcttactgg ggccaaggga ctctggtcac cgtctctagt 360
<210> 368
<211> 108
<212> PRT
<213> Mus musculus
<400> 368
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Val Phe Thr Ala
20 25 30
Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Ser Tyr Pro Leu
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 369
<211> 324
<212> DNA
<213> Mus musculus
<400> 369
gatatccaga tgacccagag cccgagcagc ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgca aagcgagcca ggatgtgttt accgcggtgg cgtggtatca gcagaaaccg 120
ggcaaagcgc cgaaactgct gatttattgg gcgagcaccc gccataccgg cgtgccgagt 180
cgctttagcg gcagcggcag cggcaccgat tttaccctga ccattagcag cctgcagccg 240
gaagattttg cgacctatta ttgccagcag tatagcagct atccgctgac ctttggcggc 300
ggcaccaaag tggaaattaa acgt 324
<210> 370
<211> 119
<212> PRT
<213> Mus musculus
<400> 370
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asn Gly Asp Ile Ile Tyr Asp Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Tyr Asp Ala Gly Asp Pro Ala Trp Phe Thr Tyr Trp Gly Gln Gly
100 105 110
Thr Leu Val Thr Val Ser Ser
115
<210> 371
<211> 357
<212> DNA
<213> Mus musculus
<400> 371
gaagtgcagc tggtgcagag cggcgcggaa gtgaaaaaac cgggcgcgag cgtgaaagtg 60
agctgcaaag cgagcggctt taacattaaa gattattata tgcattgggt gcgccaggcg 120
ccgggccagg gcctggaatg gatcggccgc attgatccgg aaaacggcga tattatttat 180
gatccgaaat ttcagggccg cgtgaccatg accaccgata ccagcaccag caccgcgtat 240
atggaactgc gcagcctgcg cagcgatgat accgcggtgt attattgcgc gtatgatgcg 300
ggcgatccgg cgtggtttac ctattggggc cagggcaccc tggtgaccgt ctcgagc 357
<210> 372
<211> 108
<212> PRT
<213> Mus musculus
<400> 372
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Val Ser Ser Ser Ile Ser Ser Ser
20 25 30
Asn Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Thr Thr Tyr
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg
100 105
<210> 373
<211> 324
<212> DNA
<213> Mus musculus
<400> 373
gatattcagc tgacccagag cccgagcttt ctgagcgcga gcgtgggcga tcgcgtgacc 60
attacctgca gcgtgagcag cagcattagc agcagcaacc tgcattggta tcagcagaaa 120
ccgggcaaag cgccgaaact gctgatttat ggcaccagca acctggcgag cggcgtgccg 180
agccgcttta gcggcagcgg cagcggcacc gaatttaccc tgaccattag cagcctgcag 240
ccggaagatt ttgcgaccta ttattgccag cagtggacca ccacctatac ctttggccag 300
ggcaccaaac tggaaattaa acgt 324
<210> 374
<211> 122
<212> PRT
<213> Mus musculus
<400> 374
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Arg Ile Asp Pro Asp Asn Gly Glu Ser Thr Tyr Val Pro Lys Phe
50 55 60
Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Gly Leu Asp Tyr Gly Asp Tyr Tyr Ala Val Asp Tyr Trp
100 105 110
Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 375
<211> 366
<212> DNA
<213> Mus musculus
<400> 375
gaagtgcagc tggtgcagag cggcgcggaa gtgaaaaaac cgggcgcgag cgtgaaagtg 60
agctgcaaag cgagcggctt taacattaaa gattattata ttcattgggt gcgccaggcg 120
ccgggccagg gcctggaatg gatgggccgc attgatccgg ataacggcga aagcacctat 180
gtgccgaaat ttcagggccg cgtgaccatg accaccgata ccagcaccag caccgcgtat 240
atggaactgc gcagcctgcg cagcgatgat accgcggtgt attattgcgc gcgcgaaggc 300
ctggattatg gcgattatta tgcggtggat tattggggcc agggcaccct ggtgaccgtc 360
tcgagc 366
<210> 376
<211> 107
<212> PRT
<213> Mus musculus
<400> 376
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Arg Leu Leu Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Asp Thr Leu Pro Tyr
85 90 95
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 377
<211> 321
<212> DNA
<213> Mus musculus
<400> 377
gacatccaga tgacccagtc tccatcctcc ctctccgcat ccgtaggcga ccgcgtaacc 60
ataacatgta gagcatctca agatatttcc aactatttga attggtacca acaaaaaccc 120
ggcaaagcac ctaaactcct catttactat acatcaagac tcctctccgg cgttccatca 180
cgattctcag gctccggctc cggcacagat ttcacactca ctatttcctc cctccaacca 240
gaagattttg caacctatta ctgtcaacaa ggcgatacac tcccatacac attcggcggc 300
ggcacaaaag ttgaaattaa a 321
<210> 378
<211> 123
<212> PRT
<213> Mus musculus
<400> 378
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 379
<211> 369
<212> DNA
<213> Mus musculus
<400> 379
gaggtgcagc tggtgcagag cggcgccgag gtaaaaaaac caggagcaag cgttaaagtt 60
tcttgtaaag caagcggata tacatttaca gattacaaca tgcattgggt aagacaagcg 120
ccaggacaag gattggaatg gatgggcgaa attaacccta atagtggagg agcaggctac 180
aatcaaaaat tcaaagggag agttacaatg acaacagaca caagcacttc aacagcatat 240
atggaactgc gatcacttag aagcgacgat acagctgtat actattgcgc acgacttggg 300
tatgatgata tatatgatga ctggtatttc gatgtttggg gccagggaac aacagttacc 360
gtctctagt 369
<210> 380
<211> 108
<212> PRT
<213> Mus musculus
<400> 380
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Thr Ser Ser
20 25 30
Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asp Phe Phe Pro
85 90 95
Ser Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 381
<211> 324
<212> DNA
<213> Mus musculus
<400> 381
gacatccagc tgacccagag ccccagcttc ctttccgcat ccgttggtga ccgagtaaca 60
atcacatgcc gcgcctcatc ttcagttaca tcttcttatc ttaattggta tcaacaaaaa 120
ccaggaaaag cacctaaact tcttatatac tctacatcta atctcgcatc aggagttccc 180
tctcgatttt caggatctgg atcaggcaca gaatttacac ttactatatc atcactccaa 240
ccagaagact tcgccactta ttactgccaa caatacgatt tttttccaag cacattcgga 300
ggaggtacaa aagtagaaat caag 324
<210> 382
<211> 121
<212> PRT
<213> Mus musculus
<400> 382
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn His Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser
115 120
<210> 383
<211> 363
<212> DNA
<213> Mus musculus
<400> 383
gaggtgcagc tggtgcagag cggcgccgag gtcaagaaac ctggagcaag cgtaaaggtt 60
agttgcaaag catctggata cacatttacc gactactaca tgaattgggt acgacaagcc 120
cctggacaaa gacttgaatg gatgggagac attaaccctt ataacgacga cactacatac 180
aatcataaat ttaaaggaag agttacaatt acaagagata catccgcatc aaccgcctat 240
atggaacttt cctcattgag atctgaagac actgctgttt attactgtgc aagagaaact 300
gccgttatta ctactaacgc tatggattac tggggtcaag gaaccactgt taccgtctct 360
agt 363
<210> 384
<211> 108
<212> PRT
<213> Mus musculus
<400> 384
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Val Ser Ser Thr Ile Ser Ser Asn
20 25 30
His Leu His Trp Phe Gln Gln Lys Pro Gly Lys Ala Pro Lys Ser Leu
35 40 45
Ile Tyr Gly Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser
50 55 60
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
65 70 75 80
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Tyr Pro
85 90 95
Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 385
<211> 324
<212> DNA
<213> Mus musculus
<400> 385
gacatccaga tgacccagtc tccatcctcc ctctcagcat ccgtaggcga tagagttaca 60
ataacatgca gcgtatcatc aactatatca tcaaatcatc ttcattggtt ccaacagaaa 120
cccggcaaag cacctaaatc acttatatac ggcacatcaa atctcgcatc aggcgttcct 180
tcaagatttt caggctctgg ctcaggcacc gactttactc ttacaatatc ctccctccaa 240
cccgaagact tcgcaaccta ttactgtcaa caatggtcct catatccact cacatttggc 300
ggcggcacaa aagtagaaat taaa 324
<210> 386
<211> 125
<212> PRT
<213> Mus musculus
<400> 386
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Phe Asn Ile Lys Asp Phe
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asn Gly Asp Thr Leu Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Lys Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ala Asp Tyr Phe His Asp Gly Thr Ser Tyr Trp Tyr Phe
100 105 110
Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser
115 120 125
<210> 387
<211> 375
<212> DNA
<213> Mus musculus
<400> 387
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctgactt caacattaaa gacttctatc tacactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gattggaagg attgatcctg agaatggtga tactttatat 180
gacccgaagt tccaggacaa ggtcaccatg accacagaca cgtccaccag cacagcctac 240
atggagctga ggagcctgag atctgacgac acggccgtgt attactgtgc gagagaggcg 300
gattatttcc acgatggtac ctcctactgg tacttcgatg tctggggccg tggcaccctg 360
gtcaccgtct ctagt 375
<210> 388
<211> 106
<212> PRT
<213> Mus musculus
<400> 388
Asp Ile Gln Leu Thr Gln Ser Pro Ser Phe Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Ile Ser Tyr Ile
20 25 30
His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr
35 40 45
Ala Thr Ser Asn Leu Ala Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
50 55 60
Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
65 70 75 80
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Ser Asp Pro Leu Thr
85 90 95
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
100 105
<210> 389
<211> 318
<212> DNA
<213> Mus musculus
<400> 389
gacatccagt tgacccagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60
atcacttgca gggccagctc aagtataagt tacatacact ggtatcagca aaaaccaggg 120
aaagccccta agctcctgat ctatgccaca tccaacctgg cttctggggt cccatcaagg 180
ttcagcggca gtggatctgg gacagaattc actctcacaa tcagcagcct gcagcctgaa 240
gattttgcaa cttattactg tcagcagtgg agtagtgacc cactcacgtt cggcggaggg 300
accaaggtgg agatcaaa 318
<210> 390
<211> 121
<212> PRT
<213> Mus musculus
<400> 390
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala Pro Lys Phe
50 55 60
Pro Gly Lys Val Thr Met Thr Thr Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 391
<211> 363
<212> DNA
<213> Mus musculus
<400> 391
gaggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60
tcctgcaagg cttctggatt cgacattaag gactactata tacactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatcggaagg gttgatcctg acaatggtga gactgaattt 180
gccccgaagt tcccgggcaa ggtcaccatg accacagaca cgtccatcag cacagcctac 240
atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagaagac 300
tacgatggta cctacacctg gtttccttat tggggccaag ggactctggt caccgtctct 360
agt 363
<210> 392
<211> 448
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 392
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Asn Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Glu Ile Asn Pro Asn Ser Gly Gly Ala Gly Tyr Asn Gln Lys Phe
50 55 60
Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Leu Gly Tyr Asp Asp Ile Tyr Asp Asp Trp Tyr Phe Asp Val
100 105 110
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
115 120 125
Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
130 135 140
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
145 150 155 160
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
165 170 175
Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
180 185 190
Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val
195 200 205
Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
210 215 220
Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
225 230 235 240
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
245 250 255
Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp
260 265 270
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
275 280 285
Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
290 295 300
Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
305 310 315 320
Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
325 330 335
Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
340 345 350
Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
355 360 365
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
370 375 380
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
385 390 395 400
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
405 410 415
Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu
420 425 430
Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 393
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 393
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr
20 25 30
Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met
35 40 45
Gly Asp Ile Asn Pro Tyr Asn Asp Asp Thr Thr Tyr Asn His Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Arg Asp Thr Ser Ala Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Thr Ala Val Ile Thr Thr Asn Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
210 215 220
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
290 295 300
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 394
<211> 450
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 394
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Asp Phe Asn Ile Lys Asp Phe
20 25 30
Tyr Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Ile Asp Pro Glu Asn Gly Asp Thr Leu Tyr Asp Pro Lys Phe
50 55 60
Gln Asp Lys Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Ala Asp Tyr Phe His Asp Gly Thr Ser Tyr Trp Tyr Phe
100 105 110
Asp Val Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr
115 120 125
Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
130 135 140
Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu
145 150 155 160
Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
165 170 175
Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
180 185 190
Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys
195 200 205
Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu
210 215 220
Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala
225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
290 295 300
Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly
450
<210> 395
<211> 446
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 395
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asp Ile Lys Asp Tyr
20 25 30
Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Arg Val Asp Pro Asp Asn Gly Glu Thr Glu Phe Ala Pro Lys Phe
50 55 60
Pro Gly Lys Val Thr Met Thr Thr Asp Thr Ser Ile Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Asp Tyr Asp Gly Thr Tyr Thr Trp Phe Pro Tyr Trp Gly
100 105 110
Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys
210 215 220
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
225 230 235 240
Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr
245 250 255
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
260 265 270
Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
275 280 285
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
290 295 300
Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
305 310 315 320
Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
325 330 335
Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
340 345 350
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
355 360 365
Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn
370 375 380
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
385 390 395 400
Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg
405 410 415
Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
420 425 430
His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445
<210> 396
<211> 445
<212> PRT
<213> 人工序列
<220>
<223> 人源化抗体序列
<400> 396
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Thr Phe Thr Asp Tyr
20 25 30
Ile Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Tyr Ile Asn Pro Tyr Asn Asp Asp Thr Glu Tyr Asn Glu Lys Phe
50 55 60
Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Ser Ile Tyr Tyr Tyr Asp Ala Pro Phe Ala Tyr Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
210 215 220
Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe
225 230 235 240
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
260 265 270
Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
275 280 285
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val
290 295 300
Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
305 310 315 320
Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335
Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
340 345 350
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
355 360 365
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
385 390 395 400
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440 445

Claims (10)

1.一种sclerostin结合剂，其交叉阻断至少一种下列抗体与sclerostin的结合：Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24。
2.权利要求1的sclerostin结合剂，其中所述sclerostin结合剂被至少一种下列抗体交叉阻断与sclerostin的结合：Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24。
3.一种sclerostin结合剂，其被至少一种下列抗体交叉阻断与sclerostin的结合：Ab-A、Ab-B、Ab-C、Ab-D、Ab-1、Ab-2、Ab-3、Ab-4、Ab-5、Ab-6、Ab-7、Ab-8、Ab-9、Ab-10、Ab-11、Ab-12、Ab-13、Ab-14、Ab-15、Ab-16、Ab-17、Ab-18、Ab-19、Ab-20、Ab-21、Ab-22、Ab-23和Ab-24。
4.权利要求1或3的sclerostin结合剂，其中所述sclerostin结合剂交叉阻断或被交叉阻断的能力是在Biacore测定法中进行检测的。
5.权利要求1或3的sclerostin结合剂，其中所述sclerostin结合剂交叉阻断或被交叉阻断的能力是在ELISA测定法中进行检测的。
6.权利要求1或3的sclerostin结合剂，其中所述sclerostin结合剂是抗体。
7.权利要求1或3的sclerostin结合剂，其中所述sclerostin结合剂可以增加哺乳动物中的骨形成、骨矿物质密度、骨矿物质含量、骨量、骨质量和骨强度中的至少一种。
8.权利要求1或3的sclerostin结合剂，其中所述sclerostin结合剂在基于细胞的矿化测定法中可以阻断sclerostin的抑制效应。
9.一种sclerostin结合剂，其中所述sclerostin结合剂在基于细胞的矿化测定法中可以阻断sclerostin的抑制效应。
10.一种sclerostin结合剂，其与Loop2表位结合。
CN201710738235.4A 2005-05-03 2006-04-28 Sclerostin结合剂 Pending CN107446043A (zh)

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US67758305P 2005-05-03 2005-05-03
US60/677,583 2005-05-03
US77684706P 2006-02-24 2006-02-24
US60/776,847 2006-02-24
US78224406P 2006-03-13 2006-03-13
US60/782,244 2006-03-13
US79264506P 2006-04-17 2006-04-17
US60/792,645 2006-04-17
US11/411,003 US7592429B2 (en) 2005-05-03 2006-04-25 Sclerostin-binding antibody
US11/411,003 2006-04-25
CN200680024330.8A CN101287756B (zh) 2005-05-03 2006-04-28 硬化素结合剂

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